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Liu Z, Xue H, Wang Z, Zhao Y, Xu S, Dong X. Cyclin Y interacts with Chk1 to activate RRM2/STAT3 signaling and promotes radioresistance in non-small cell lung cancer. Int J Biol Sci 2025; 21:1999-2011. [PMID: 40083692 PMCID: PMC11900816 DOI: 10.7150/ijbs.106925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/07/2025] [Indexed: 03/16/2025] Open
Abstract
Radioresistance is one of the main reasons for the recurrence and metastasis of non-small cell lung cancer. Cyclin Y has been implicated in various cellular processes such as cell growth, proliferation, autophagy, and tumor progression. However, the function and regulatory mechanism of Cyclin Y in lung cancer radioresistance remain poorly understood. In this study, we find that Cyclin Y is overexpressed in non-small cell lung cancer and correlates with poor prognosis. Furthermore, knockdown of Cyclin Y results in inhibited cell growth and proliferation, increases DNA damage, impairs DNA damage repair, and enhances radiosensitivity in vitro and in vivo. Mechanistically, we uncover that Cyclin Y interacts with Chk1 and positively regulate both the mRNA and protein levels of RRM2, resulting in increased STAT3 phosphorylation. Rescue experiments confirm that the effects of Cyclin Y on lung cancer are mediated partially by RRM2. Collectively, we reveal for the first time that Cyclin Y promotes lung cancer radioresistance by binding to Chk1 to activate RRM2/STAT3 signaling, indicating that targeting Cyclin Y may be a promising strategy for enhancing the efficacy of radiotherapy in the treatment of non-small cell lung cancer.
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Affiliation(s)
- Zhiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
| | - Huichan Xue
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
| | - Zhi Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
| | - Ye Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
| | - Shuangbing Xu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Qi J, Li L, Gao B, Dai K, Shen K, Wu X, Li H, Yu Z, Wang Z, Wang Z. Prognostic prediction and immune checkpoint profiling in glioma patients through neddylation-associated features. Gene 2024; 930:148835. [PMID: 39127414 DOI: 10.1016/j.gene.2024.148835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 07/11/2024] [Accepted: 08/07/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND Gliomas are the most common primary malignant tumours of the central nervous system, and neddylation may be a potential target for the treatment of gliomas. Our study analysed neddylation's potential role in gliomas of different pathological types and its correlation with immunotherapy. METHODS Genes required for model construction were sourced from existing literature, and their expression data were extracted from the TCGA and CGGA databases. LASSO regression was employed to identify genes associated with the prognosis of glioma patients in TCGA and to establish a clinical prognostic model. Biological changes in glioma cell lines following intervention with hub genes were evaluated using the CCK-8 assay and transwell assay. The genes implicated in the model construction were validated across various cell lines using Western blot. We conducted analyses to examine correlations between model scores and clinical data, tumor microenvironments, and immune checkpoints. Furthermore, we investigated potential differences in molecular functions and mechanisms among different groups. RESULTS We identified 249 genes from the Reactome database and analysed their expression profiles in the TCGA and CGGA databases. After using LASSO-Cox, four genes (BRCA1, BIRC5, FBXL16 and KLHL25, p < 0.05) with significant correlations were identified. We selected FBXL16 for validation in in vitro experiments. Following FBXL16 overexpression, the proliferation, migration, and invasion abilities of glioma cell lines all showed a decrease. Then, we constructed the NEDD Index for gliomas. The nomogram indicated that this model could serve as an independent prognostic marker. Analysis of the tumour microenvironment and immune checkpoints revealed that the NEDD index was also correlated with immune cell infiltration and the expression levels of various immune checkpoints. CONCLUSION The NEDD index can serve as a practical tool for predicting the prognosis of glioma patients, and it is correlated with immune cell infiltration and the expression levels of immune checkpoints.
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Affiliation(s)
- Juxing Qi
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Longyuan Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Bixi Gao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Kun Dai
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Kecheng Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Xin Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Zhengquan Yu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China
| | - Zongqi Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China.
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou, 215006, China.
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Harbi E, Aschner M. Role of BRCA1 in glioblastoma etiology. Cell Oncol (Dordr) 2024; 47:2091-2098. [PMID: 39656422 DOI: 10.1007/s13402-024-01024-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2024] [Indexed: 01/11/2025] Open
Abstract
BRCA1 (Breast Cancer 1) is a tumor suppressor gene with a role in DNA repair by Homologous Recombination (HR), and maintenance of genomic stability that is frequently investigated in breast, prostate, and ovarian cancers. BRCA1 mutations or dysregulation in glioblastoma can lead to impaired DNA repair mechanisms, resulting in tumor progression and resistance to standard therapies. Several studies have shown that BRCA1 expression is altered, albeit rarely, in glioblastoma, leading to poor prognosis and increased tumor aggressiveness. In addition, the communication of BRCA1 with other molecular pathways such as p53 and PTEN further complicates its role in glioblastoma pathogenesis. Targeting BRCA1-related pathways in these cases has shown the potential to improve the efficacy of standard treatments, including radiotherapy and chemotherapy. The development of (Poly (ADP-ribose) Polymerase) PARP inhibitors that exploit the lack of HR also offers a therapeutic approach to glioblastoma patients with BRCA1 mutations. Despite these advances, the heterogeneity of glioblastoma and its complex tumor microenvironment make the translation of such approaches into clinical practice still challenging, and there is an "unmet need". This review discusses the current mechanisms of etiology and potential treatment of BRCA1-related glioblastoma.
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Affiliation(s)
- Emirhan Harbi
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA
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Xuan X, Li Y, Huang C, Zhang Y. Regorafenib promotes antitumor progression in melanoma by reducing RRM2. iScience 2024; 27:110993. [PMID: 39435141 PMCID: PMC11492136 DOI: 10.1016/j.isci.2024.110993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 07/30/2024] [Accepted: 09/16/2024] [Indexed: 10/23/2024] Open
Abstract
Melanoma is a malignant tumor with a terrible prognosis. Although so many therapies are used for melanoma, the overall survival rate is still poor globally. Novel therapies are still required. In our study, the role and potential mechanism of regorafenib in melanoma are explored. Regorafenib has the ability to limit the growth, invasion, and metastasis of melanoma cells but to upregulate apoptosis-prompting markers (cleaved-PARP and Bax). RRM2 is identified to be the downstream target of regorafenib by RNA sequencing. In addition, we discovered that RRM2 inhibition and regorafenib have comparable effects on melanoma cells. Rescue experiments showed that RRM2 is crucial in regulating regorafenib's anti-melanoma progression. Moreover, ERK/E2F3 signaling influences regorafenib's ability to suppress melanoma cell growth. Ultimately, regorafenib significantly inhibits tumor growth in vivo. In conclusion, our finding demonstrated that regorafenib promotes antitumor progression in melanoma by reducing RRM2.
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Affiliation(s)
- Xiuyun Xuan
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Yanqiu Li
- Department of Dermatology, Hubei NO.3 People’s Hospital of Jianghan University, Wuhan 430033, Hubei, China
| | - Changzheng Huang
- Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
| | - Yong Zhang
- Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China
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Zhang J, Wu Q, Xie Y, Li F, Wei H, Jiang Y, Qiao Y, Li Y, Sun Y, Huang H, Ge M, Zhao D, Dong Z, Liu K. Ribonucleotide reductase small subunit M2 promotes the proliferation of esophageal squamous cell carcinoma cells via HuR-mediated mRNA stabilization. Acta Pharm Sin B 2024; 14:4329-4344. [PMID: 39525580 PMCID: PMC11544187 DOI: 10.1016/j.apsb.2024.07.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/11/2024] [Accepted: 07/23/2024] [Indexed: 11/16/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC), a malignancy of the digestive system, is highly prevalent and the primary cause of cancer-related deaths worldwide due to the lack of early diagnostic biomarkers and effective therapeutic targets. Dysregulated ribonucleotide reductase (RNR) expression has been confirmed to be causally linked to tumorigenesis. This study demonstrated that ribonucleotide reductase small subunit M2 (RRM2) is significantly upregulated in ESCC tissue and that its expression is negatively correlated with clinical outcomes. Mechanistically, HuR promotes RRM2 mRNA stabilization by binding to the adenine/uridine (AU)-rich elements (AREs) within the 3'UTR, resulting in persistent overexpression of RRM2. Furthermore, bifonazole is identified as an inhibitor of HuR via computational screening and molecular docking analysis. Bifonazole disrupts HuR-ARE interactions by competitively binding to HuR at F65, R97, I103, and R153 residues, resulting in reduced RRM2 expression. Furthermore, bifonazole exhibited antitumor effects on ESCC patient-derived xenograft (PDX) models by decreasing RRM2 expression and the dNTP pool. In summary, this study reveals the interaction network among HuR, RRM2, and bifonazole and demonstrated that bifonazole is a potential therapeutic compound for ESCC through inhibition of the HuR/RRM2 axis.
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Affiliation(s)
- Jing Zhang
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Qiong Wu
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Yifei Xie
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou 450052, China
| | - Feng Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Huifang Wei
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Yanan Jiang
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Yan Qiao
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
| | - Yinhua Li
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Yanan Sun
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Han Huang
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Mengmeng Ge
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Dengyun Zhao
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
| | - Zigang Dong
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450000, China
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou 450000, China
| | - Kangdong Liu
- Pathophysiology Department, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450000, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou 450000, China
- Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou 450000, China
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Li Z, Jin Y, Zhang P, Zhang XA, Yi G, Zheng H, Yuan X, Wang X, Xu H, Qiu X, Chen C, Que T, Huang G. A Four-Gene Panel for the Prediction of Prognosis and Immune Cell Enrichment in Gliomas. Mol Biotechnol 2024; 66:2308-2321. [PMID: 37644261 DOI: 10.1007/s12033-023-00820-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 07/05/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUNDS Gliomas is a deadly disease without effective therapy. Although immunotherapy has provided novel choices for glioma treatment, the curative efficacy is unsatisfactory due to the complex immune micro-environment and the heterogeneity of the disease. Therefore, it is urgent to identify effective biomarkers and therapeutic targets. METHODS Overall survival, gene ontology (GO), Kyoto Encyclopedia of Genes, and Genomes (KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and immune infiltration were analyzed by bioinformatics software with The Cancer Genome Atlas (TCGA) database. RESULTS Based on the TCGA database and protein-protein interaction (PPI) analysis revealed a four-gene panels [DNA topoisomerase II alpha (TOP2A); ribonucleotide reductase regulatory subunit M2 (RRM2); kinesin family member 20 A (KIF20A) and DLG associated protein 5 (DLGAP5)], which correlated with poor prognosis, including overall survival (OS), disease specific survival (DSS) and progress free interval (PFI), mitosis, cell cycle, Th2 cells and macrophages enrichment. The four-gene panels correlates with the biomarkers of Th2 cells, macrophages tumor-associated macrophages (TAMs) and the immune checkpoint molecules in gliomas. CONCLUSION The four-gene panels represented a novel prognostic indicator and potential therapeutic target for the treatment of glioma. In addition, the four-gene panels might contribute to enhance the efficacy of immunotherapy in glioma.
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Affiliation(s)
- Zhiyong Li
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Yinghui Jin
- Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Peidong Zhang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Xi-An Zhang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Guozhong Yi
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Haojie Zheng
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Xi Yuan
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Xiaoyan Wang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Haiyan Xu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Xiaoyu Qiu
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Chao Chen
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China
| | - Tianshi Que
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China.
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
| | - Guanglong Huang
- Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, 510515, Guangzhou, Guangdong, People's Republic of China.
- Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.
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Zhao W, Zhou L, Zhao W, Yang H, Lu Z, Zhang L, Zhang Y, Xie Y, Lu H, Han W, He J, Qiu X, Jia F, Zhao W, Zhang B, Wang Z. The combination of temozolomide and perifosine synergistically inhibit glioblastoma by impeding DNA repair and inducing apoptosis. Cell Death Discov 2024; 10:315. [PMID: 38977680 PMCID: PMC11231210 DOI: 10.1038/s41420-024-02085-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/13/2024] [Accepted: 06/25/2024] [Indexed: 07/10/2024] Open
Abstract
Temozolomide (TMZ) is widely utilized as the primary chemotherapeutic intervention for glioblastoma. However, the clinical use of TMZ is limited by its various side effects and resistance to chemotherapy. The present study revealed the synergistic inhibition of glioblastoma through the combined administration of TMZ and perifosine. This combination therapy markedly diminished BRCA1 expression, resulting in the suppression of DNA repair mechanisms. Furthermore, the combination of TMZ and perifosine elicited caspase-dependent apoptosis, decreasing glioblastoma cell viability and proliferation. The observed synergistic effect of this combination therapy on glioblastoma was validated in vivo, as evidenced by the substantial reduction in glioblastoma xenograft growth following combined treatment with TMZ and perifosine. In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment.
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Affiliation(s)
- Wenpeng Zhao
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Liwei Zhou
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Wentao Zhao
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Huiying Yang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Zhenwei Lu
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350122, China
| | - Liang Zhang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Yaya Zhang
- Department of Medical Oncology, the First Affiliated Hospital of Xiamen University, Xiamen, 361003, China
| | - Yuanyuan Xie
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Hanwen Lu
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Wanhong Han
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Jiawei He
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Xiansheng Qiu
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, 350122, China
| | - Fang Jia
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Wujie Zhao
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Bingchang Zhang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China.
| | - Zhanxiang Wang
- Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China.
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Hua D, Huang W, Xu W, Zhang Y, Xie Q, Li P, Sheng Y. Targeting of G protein-coupled receptor 39 alleviates angiotensin II-induced renal damage by reducing ribonucleotide reductase M2. Exp Cell Res 2024; 440:114102. [PMID: 38821252 DOI: 10.1016/j.yexcr.2024.114102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/26/2024] [Accepted: 05/26/2024] [Indexed: 06/02/2024]
Abstract
Renal fibrosis, apoptosis and autophagy are the main pathological manifestations of angiotensin II (Ang II)-induced renal injury. G protein-coupled receptor 39 (GPR39) is highly expressed in various tissues including the kidney, but its role in the kidney is entirely unclear. This study was performed to investigate the underlying mechanism by which knockdown of GPR39 alleviated Ang II-induced renal injury. In vivo, GPR39 knockout (KO) mice were constructed and infused with Ang II for 4 weeks, followed by renal function tests. In vitro, Ang II-induced cells were treated with si-GPR39 for 48 h. Fibrosis, apoptosis and autophagy were detected in both cells and mice. The underlying mechanism was sought by mRNA transcriptome sequencing and validated in vitro. GPR39 was upregulated in renal tissues of mice with Ang II-mediated renal injury. Knockdown of GPR39 ameliorated renal fibrosis, apoptosis, and autophagy, and decreased the expression of ribonucleotide reductase M2 (RRM2). In vitro, knockdown of GPR39 was also identified to improve the Ang II-induced cell fibrosis, apoptosis, and autophagy. mRNA transcriptome results showed that knockout of GPR39 reduced the expression of RRM2 in Ang II-induced kidney tissue. Activation of RRM2 could reverse the therapeutic effect of GPR39 knockout, and the inhibitor of RRM2 could improve the cell fibrosis, apoptosis and autophagy caused by GPR39 agonist. These results indicated that targeting of GPR39 could alleviate Ang II-induced renal fibrosis, apoptosis, and autophagy via reduction of RRM2 expression, and GPR39 may serve as a potential target for Ang II-induced renal injury.
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Affiliation(s)
- Dongxu Hua
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, PR China; Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, PR China
| | - Wanlin Huang
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, PR China
| | - Wenna Xu
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, PR China
| | - Yue Zhang
- Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, PR China; Department of Cardiology, Jiangsu Province People's Hospital, Nanjing, Jiangsu, PR China
| | - Qiyang Xie
- Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, PR China; Department of Cardiology, Jiangsu Province People's Hospital, Nanjing, Jiangsu, PR China
| | - Peng Li
- Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, PR China; Department of Cardiology, Jiangsu Province People's Hospital, Nanjing, Jiangsu, PR China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, PR China.
| | - Yanhui Sheng
- Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, PR China; Department of Cardiology, Jiangsu Province People's Hospital, Nanjing, Jiangsu, PR China.
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9
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Wang Y, Chen R, Zhang J, Zeng P. A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer. PLoS One 2024; 19:e0299949. [PMID: 38635758 PMCID: PMC11025932 DOI: 10.1371/journal.pone.0299949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 02/19/2024] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND Although there is evidence that ribonucleotide reductase subunit M2 (RRM2) is associated with numerous cancers, pan-cancer analysis has seldom been conducted. This study aimed to explore the potential carcinogenesis of RRM2 in pan-cancer using datasets from The Cancer Genome Atlas (TCGA). METHODS Data from the UCSC Xena database were analyzed to investigate the differential expression of RRM2 across multiple cancer types. Clinical data such as age, race, sex, tumor stage, and status were acquired to analyze the influence of RRM2 on the clinical characteristics of the patients. The role of RRM2 in the onset and progression of multiple cancers has been examined in terms of genetic changes at the molecular level, including tumor mutational burden (TMB), microsatellite instability (MSI), biological pathway changes, and the immune microenvironment. RESULTS RRM2 was highly expressed in most cancers, and there was an obvious correlation between RRM2 expression and patient prognosis. RRM2 expression is associated with the infiltration of diverse immune and endothelial cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). Moreover, the cell cycle is involved in the functional mechanisms of RRM2. CONCLUSIONS Our pan-cancer study provides a comprehensive understanding of the carcinogenesis of RRM2 in various tumors.
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Affiliation(s)
- Yong Wang
- Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China
| | - Rong Chen
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China
| | - Jing Zhang
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China
| | - Peng Zeng
- Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu, China
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10
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Mahieu CI, Mancini AG, Vikram EP, Planells-Palop V, Joseph NM, Tward AD. ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma. Mol Cancer Res 2024; 22:152-168. [PMID: 37930255 PMCID: PMC10831340 DOI: 10.1158/1541-7786.mcr-23-0746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 09/29/2023] [Accepted: 11/02/2023] [Indexed: 11/07/2023]
Abstract
11q13 amplification is a frequent event in human cancer and in particular in squamous cell carcinomas (SCC). Despite almost invariably spanning 10 genes, it is unclear which genetic components of the amplicon are the key driver events in SCC. A combination of computational, in vitro, ex vivo, and in vivo models leveraging efficient primary human keratinocyte genome editing by Cas9-RNP electroporation, identified ORAOV1, CCND1, and MIR548K as the critical drivers of the amplicon in head and neck SCC. CCND1 amplification drives the cell cycle in a CDK4/6/RB1-independent fashion and may confer a novel dependency on RRM2. MIR548K contributes to epithelial-mesenchymal transition. Finally, we identify ORAOV1 as an oncogene that acts likely via its ability to modulate reactive oxygen species. Thus, the 11q13 amplicon drives SCC through at least three independent genetic elements and suggests therapeutic targets for this morbid and lethal disease. IMPLICATIONS This work demonstrates novel mechanisms and ways to target these mechanisms underlying the most common amplification in squamous cell carcinoma, one of the most prevalent and deadly forms of human cancer.
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Affiliation(s)
- Céline I. Mahieu
- Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, Calfornia
| | | | - Ellee P. Vikram
- Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, Calfornia
| | - Vicente Planells-Palop
- Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, Calfornia
| | - Nancy M. Joseph
- Department of Pathology, University of California San Francisco, San Francisco, California
| | - Aaron D. Tward
- Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, Calfornia
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11
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Zuo Z, Zhou Z, Chang Y, Liu Y, Shen Y, Li Q, Zhang L. Ribonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer. Genes Dis 2024; 11:218-233. [PMID: 37588202 PMCID: PMC10425756 DOI: 10.1016/j.gendis.2022.11.022] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 10/26/2022] [Accepted: 11/14/2022] [Indexed: 12/29/2022] Open
Abstract
Ribonucleotide reductase M2 (RRM2) is a small subunit in ribonucleotide reductases, which participate in nucleotide metabolism and catalyze the conversion of nucleotides to deoxynucleotides, maintaining the dNTP pools for DNA biosynthesis, repair, and replication. RRM2 performs a critical role in the malignant biological behaviors of cancers. The structure, regulation, and function of RRM2 and its inhibitors were discussed. RRM2 gene can produce two transcripts encoding the same ORF. RRM2 expression is regulated at multiple levels during the processes from transcription to translation. Moreover, this gene is associated with resistance, regulated cell death, and tumor immunity. In order to develop and design inhibitors of RRM2, appropriate strategies can be adopted based on different mechanisms. Thus, a greater appreciation of the characteristics of RRM2 is a benefit for understanding tumorigenesis, resistance in cancer, and tumor microenvironment. Moreover, RRM2-targeted therapy will be more attention in future therapeutic approaches for enhancement of treatment effects and amelioration of the dismal prognosis.
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Affiliation(s)
- Zanwen Zuo
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), and School of Food and Biological Engineering, Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Zerong Zhou
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), and School of Food and Biological Engineering, Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Yuzhou Chang
- Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
| | - Yan Liu
- School of Agriculture and Biology, and Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yuping Shen
- College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou, Hunan 425199, China
| | - Qizhang Li
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- National “111” Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), and School of Food and Biological Engineering, Hubei University of Technology, Wuhan, Hubei 430068, China
| | - Lei Zhang
- Innovative Drug R&D Center, College of Life Sciences, Huaibei Normal University, Huaibei, Anhui 235000, China
- Department of Pharmaceutical Botany, School of Pharmacy, Naval Medical University, Shanghai 200433, China
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12
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Giang LH, Wu KS, Lee WC, Chu SS, Do AD, Changou CA, Tran HM, Hsieh TH, Chen HH, Hsieh CL, Sung SY, Yu AL, Yen Y, Wong TT, Chang CC. Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor. J Exp Clin Cancer Res 2023; 42:346. [PMID: 38124207 PMCID: PMC10731702 DOI: 10.1186/s13046-023-02911-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/19/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT. METHODS Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. RESULTS RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through apoptosis in ATRT cells. CONCLUSIONS Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT.
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Affiliation(s)
- Le Hien Giang
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
- Department of Biology and Genetics, Hai Phong University of Medicine and Pharmacy, Hai Phong, 180000, Vietnam
| | - Kuo-Sheng Wu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Wei-Chung Lee
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan
| | - Shing-Shung Chu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Anh Duy Do
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
- Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, 700000, Vietnam
| | - Chun A Changou
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan
- The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - Huy Minh Tran
- Department of Neurosurgery, Faculty of Medicine, University of Medicine and Pharmacy, Ho Chi Minh City, 700000, Vietnam
| | - Tsung-Han Hsieh
- Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, 110, Taiwan
| | - Hsin-Hung Chen
- Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, 112, Taiwan
| | - Chia-Ling Hsieh
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan
- Laboratory of Translational Medicine, Development Center for Biotechnology, Taipei, 115, Taiwan
| | - Shian-Ying Sung
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan
| | - Alice L Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, 333, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan
| | - Yun Yen
- The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan
| | - Tai-Tong Wong
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei, 110, Taiwan
- Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital and Taipei Neuroscience Institute, Taipei Medical University, Taipei, 110, Taiwan
- Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 110, Taiwan
- TMU Research Center for Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Che-Chang Chang
- International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.
- Neuroscience Research Center, Taipei Medical University Hospital, Taipei, 110, Taiwan.
- TMU Research Center for Cancer Translational Medicine, Taipei Medical University, Taipei, 110, Taiwan.
- The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 6F., Education & Research Building, Shuang-Ho Campus, No. 301, Yuantong Rd., Zhonghe Dist., New Taipei City, 23564, Taiwan.
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13
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Liu X, Zhou Q, Bai D, Schrier J. WITHDRAWN: Elevated glucose promotes DNA replication and cancer cell growth through pRB-E2F1. RESEARCH SQUARE 2023:rs.3.rs-3126261. [PMID: 37502888 PMCID: PMC10371085 DOI: 10.21203/rs.3.rs-3126261/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
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14
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Zhang R, Wang C, Zheng X, Li S, Zhang W, Kang Z, Yin S, Chen J, Chen F, Li W. Warburg effect-related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma. Cancer Med 2023; 12:20639-20654. [PMID: 37864422 PMCID: PMC10660605 DOI: 10.1002/cam4.6627] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 09/25/2023] [Accepted: 10/04/2023] [Indexed: 10/22/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM), the most common primary malignant brain tumor, has a poor prognosis, with a median survival of only 14.6 months. The Warburg effect is an abnormal energy metabolism, which is the main cause of the acidic tumor microenvironment. This study explored the role of the Warburg effect in the prognosis and immune microenvironment of GBM. METHODS A prognostic risk score model of Warburg effect-related genes (Warburg effect signature) was constructed using GBM cohort data from The Cancer Genome Atlas. Cox analysis was performed to identify independent prognostic factors. Next, the nomogram was built to predict the prognosis for GBM patients. Finally, the drug sensitivity analysis was utilized to find the drugs that specifically target Warburg effect-related genes. RESULTS Age, radiotherapy, chemotherapy, and WRGs score were confirmed as independent prognostic factors for GBM by Cox analyses. The C-index (0.633 for the training set and 0.696 for the validation set) and area under curve (>0.7) indicated that the nomogram exhibited excellent performance. The calibration curve also indicates excellent consistency of the nomogram between predictions and actual observations. In addition, immune microenvironment analysis revealed that patients with high WRGs scores had high immunosuppressive scores, a high abundance of immunosuppressive cells, and a low response to immunotherapy. The Cell Counting Kit-8 assays showed that the drugs targeting Warburg effect-related genes could inhibit the GBM cells growth in vitro. CONCLUSION Our research showed that the Warburg effect is connected with the prognosis and immune microenvironment of GBM. Therefore, targeting Warburg effect-related genes may provide novel therapeutic options.
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Affiliation(s)
- Rong Zhang
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Can Wang
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Xiaohong Zheng
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Shenglan Li
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Weichunbai Zhang
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Zhuang Kang
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Shuo Yin
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Jinyi Chen
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Feng Chen
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Wenbin Li
- Department of Neuro‐Oncology, Cancer Center, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
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15
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Chen C, Xue N, Liu K, He Q, Wang C, Guo Y, Tian J, Liu X, Pan Y, Chen G. USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2. Mol Carcinog 2023; 62:1518-1530. [PMID: 37341611 DOI: 10.1002/mc.23593] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 05/16/2023] [Accepted: 06/05/2023] [Indexed: 06/22/2023]
Abstract
RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin-specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non-small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.
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Affiliation(s)
- Congcong Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, P.R. China
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, P.R. China
| | - Ning Xue
- Department of Acupuncture, Jurong Hospital Affiliated to Jiangsu University, Zhenjiang, P.R. China
| | - Kangshou Liu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, P.R. China
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, P.R. China
| | - Qiang He
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, P.R. China
| | - Cong Wang
- School of Biopharmacy, China Pharmaceutical University, Nanjing, P.R. China
| | - Yanguan Guo
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, P.R. China
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, P.R. China
| | - Jiaxin Tian
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, P.R. China
| | - Xinjian Liu
- Department of Pathogen Biology, Key Laboratory of Antibody Technique of National Health Commission of China, Nanjing Medical University, Nanjing, P.R. China
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, P.R. China
| | - Guo Chen
- Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, P.R. China
- School of Biopharmacy, China Pharmaceutical University, Nanjing, P.R. China
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16
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Previtali V, Myers SH, Poppi L, Wynne K, Casamassima I, Girotto S, Di Stefano G, Farabegoli F, Roberti M, Oliviero G, Cavalli A. Preomic profile of BxPC-3 cells after treatment with BRC4. J Proteomics 2023; 288:104983. [PMID: 37536521 DOI: 10.1016/j.jprot.2023.104983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/26/2023] [Accepted: 07/26/2023] [Indexed: 08/05/2023]
Abstract
BRCA2 and RAD51 are two proteins that play a central role in homologous recombination (HR) and DNA double strand break (DSB) repair. BRCA2 assists RAD51 fibrillation and defibrillation through binding with its eight BRC repeats, with BRC4 being one of the most efficient and best characterized. RAD51 inactivation by small molecules has been proposed as a strategy to impair BRCA2/RAD51 binding and, ultimately, the HR pathway, with the aim of making cancer cells more sensitive to PARP inhibitors (PARPi). This strategy, which mimics a synthetic lethality (SL) approach, has been successfully performed in vitro by using the myristoylated derivative of BRC4 (myr-BRC4), designed for a more efficient cell entry. The present study applies a method to obtain a proteomic fingerprint after cellular treatment with the myr-BRC4 peptide using a mass spectroscopy (MS) proteomic approach. (Data are available via ProteomeXchange with identifier PXD042696.) We performed a comparative proteomic profiling of the myr-BRC4 treated vs. untreated BxPC-3 pancreatic cancer cells and evaluated the differential expression of proteins. Among the identified proteins, we focused our attention on proteins shared by both the RAD51 and the BRCA2 interactomes, and on those whose reduction showed high statistical significance. Three downregulated proteins were identified (FANCI, FANCD2, and RPA3), and protein downregulation was confirmed through immunoblotting analysis, validating the MS approach. Our results suggest that, being a direct consequence of myr-BRC4 treatment, the detection of FANCD2, FANCI, and RPA3 downregulation could be used as an indicator for monitoring HR impairment. SIGNIFICANCE: RAD51's inhibition has gained increasing attention because of its possible implications in personalized medicine through the SL approach. Chemical disruption of protein-protein interactions (PPIs) between RAD51 and BRCA2, or some of its partner proteins, could potentiate PARPi DNA damage-induced cell death. This could have application for difficult to treat cancers, such as BRCA-competent and olaparib (PARPi) resistant pancreatic adenocarcinoma. Despite RAD51 being a widely studied target, researchers still lack detailed mechanistic information. This has stifled progress in the field with only a few RAD51 inhibitors having been identified, none of which have gained regulatory approval. Nevertheless, the peptide BRC4 is one of the most specific and best characterized RAD51 binder and inhibitor reported to date. Our study is the first to report the proteomic fingerprint consequent to cellular treatment of myr-BRC4, to offer a reference for the discovery of specific protein/pathway alterations within DNA damage repair. Our results suggest that, being a direct consequence of myr-BRC4 treatment, and ultimately ofBRCA2/RAD51 disruption, the detection of FANCD2, FANCI, and RPA3 downregulation could be used as an indicator for monitoring DNA damage repair impairment and therefore be used to potentiate the development of new effective therapeutic strategies.
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Affiliation(s)
- Viola Previtali
- Computational & Chemical Biology, Istituto Italiano di Tecnologia, 16163 Genova, Italy
| | - Samuel H Myers
- Computational & Chemical Biology, Istituto Italiano di Tecnologia, 16163 Genova, Italy
| | - Laura Poppi
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Kieran Wynne
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland
| | - Irene Casamassima
- Computational & Chemical Biology, Istituto Italiano di Tecnologia, 16163 Genova, Italy
| | - Stefania Girotto
- Computational & Chemical Biology, Istituto Italiano di Tecnologia, 16163 Genova, Italy; Structural Biophysics and Translational Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
| | - Giuseppina Di Stefano
- Department of Surgical and Medical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Fulvia Farabegoli
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Marinella Roberti
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Giorgio Oliviero
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield Dublin 4, Ireland
| | - Andrea Cavalli
- Computational & Chemical Biology, Istituto Italiano di Tecnologia, 16163 Genova, Italy; Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
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17
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Corrales-Guerrero S, Cui T, Castro-Aceituno V, Yang L, Nair S, Feng H, Venere M, Yoon S, DeWees T, Shen C, Williams TM. Inhibition of RRM2 radiosensitizes glioblastoma and uncovers synthetic lethality in combination with targeting CHK1. Cancer Lett 2023; 570:216308. [PMID: 37482342 DOI: 10.1016/j.canlet.2023.216308] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/29/2023] [Accepted: 07/11/2023] [Indexed: 07/25/2023]
Abstract
Glioblastoma (GBM) is an aggressive malignant primary brain tumor. Radioresistance largely contributes to poor clinical outcomes in GBM patients. We targeted ribonucleotide reductase subunit 2 (RRM2) with triapine to radiosensitize GBM. We found RRM2 is associated with increasing tumor grade, is overexpressed in GBM over lower grade gliomas and normal tissue, and is associated with worse survival. We found silencing or inhibition of RRM2 by siRNA or triapine sensitized GBM cells to ionizing radiation (IR) and delayed resolution of IR-induced γ-H2AX nuclear foci. In vivo, triapine and IR reduced tumor growth and increased mouse survival. Intriguingly, triapine led to RRM2 upregulation and CHK1 activation, suggesting a CHK1-dependent RRM2 upregulation following RRM2 inhibition. Consistently, silencing or inhibition of CHK1 with rabusertib abolished the triapine-induced RRM2 upregulation. Accordingly, combining rabusertib and triapine resulted in synthetic lethality in GBM cells. Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM.
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Affiliation(s)
- Sergio Corrales-Guerrero
- Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Tiantian Cui
- Department of Radiation Oncology, City of Hope, Duarte, CA, USA
| | | | - Linlin Yang
- Department of Radiation Oncology, City of Hope, Duarte, CA, USA
| | - Sindhu Nair
- Department of Radiation Oncology, City of Hope, Duarte, CA, USA
| | - Haihua Feng
- Department of Radiation Oncology, City of Hope, Duarte, CA, USA
| | - Monica Venere
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Columbus, OH, USA
| | - Stephanie Yoon
- Department of Radiation Oncology, City of Hope, Duarte, CA, USA
| | - Todd DeWees
- Division of Biostatistics, City of Hope, Duarte, CA, USA
| | - Changxian Shen
- Department of Radiation Oncology, City of Hope, Duarte, CA, USA
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18
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Miyai M, Iwama T, Hara A, Tomita H. Exploring the Vital Link Between Glioma, Neuron, and Neural Activity in the Context of Invasion. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:669-679. [PMID: 37286277 DOI: 10.1016/j.ajpath.2023.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 02/15/2023] [Accepted: 02/23/2023] [Indexed: 06/09/2023]
Abstract
Because of their ability to infiltrate normal brain tissue, gliomas frequently evade microscopic surgical excision. The histologic infiltrative property of human glioma has been previously characterized as Scherer secondary structures, of which the perivascular satellitosis is a prospective target for anti-angiogenic treatment in high-grade gliomas. However, the mechanisms underlying perineuronal satellitosis remain unclear, and therapy remains lacking. Our knowledge of the mechanism underlying Scherer secondary structures has improved over time. New techniques, such as laser capture microdissection and optogenetic stimulation, have advanced our understanding of glioma invasion mechanisms. Although laser capture microdissection is a useful tool for studying gliomas that infiltrate the normal brain microenvironment, optogenetics and mouse xenograft glioma models have been extensively used in studies demonstrating the unique role of synaptogenesis in glioma proliferation and identification of potential therapeutic targets. Moreover, a rare glioma cell line is established that, when transplanted in the mouse brain, can replicate and recapitulate the human diffuse invasion phenotype. This review discusses the primary molecular causes of glioma, its histopathology-based invasive mechanisms, and the importance of neuronal activity and interactions between glioma cells and neurons in the brain microenvironment. It also explores current methods and models of gliomas.
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Affiliation(s)
- Masafumi Miyai
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Neurosurgery, Hashima City Hospital, Gifu, Japan; Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Toru Iwama
- Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
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19
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Kałuzińska-Kołat Ż, Kołat D, Kośla K, Płuciennik E, Bednarek AK. Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations. World J Stem Cells 2023; 15:302-322. [PMID: 37342224 PMCID: PMC10277965 DOI: 10.4252/wjsc.v15.i5.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/03/2023] [Accepted: 03/08/2023] [Indexed: 05/26/2023] Open
Abstract
Literature data on glioblastoma ongoingly underline the link between metabolism and cancer stemness, the latter is one responsible for potentiating the resistance to treatment, inter alia due to increased invasiveness. In recent years, glioblastoma stemness research has bashfully introduced a key aspect of cytoskeletal rearrangements, whereas the impact of the cytoskeleton on invasiveness is well known. Although non-stem glioblastoma cells are less invasive than glioblastoma stem cells (GSCs), these cells also acquire stemness with greater ease if characterized as invasive cells and not tumor core cells. This suggests that glioblastoma stemness should be further investigated for any phenomena related to the cytoskeleton and metabolism, as they may provide new invasion-related insights. Previously, we proved that interplay between metabolism and cytoskeleton existed in glioblastoma. Despite searching for cytoskeleton-related processes in which the investigated genes might have been involved, not only did we stumble across the relation to metabolism but also reported genes that were found to be implicated in stemness. Thus, dedicated research on these genes in GSCs seems justifiable and might reveal novel directions and/or biomarkers that could be utilized in the future. Herein, we review the previously identified cytoskeleton/metabolism-related genes through the prism of glioblastoma stemness.
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Affiliation(s)
- Żaneta Kałuzińska-Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland.
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz 90-136, Lodzkie, Poland
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz 90-752, Lodzkie, Poland
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20
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Perrault EN, Shireman JM, Ali ES, Lin P, Preddy I, Park C, Budhiraja S, Baisiwala S, Dixit K, James CD, Heiland DH, Ben-Sahra I, Pott S, Basu A, Miska J, Ahmed AU. Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production. SCIENCE ADVANCES 2023; 9:eade7236. [PMID: 37196077 PMCID: PMC10191446 DOI: 10.1126/sciadv.ade7236] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 04/13/2023] [Indexed: 05/19/2023]
Abstract
During therapy, adaptations driven by cellular plasticity are partly responsible for driving the inevitable recurrence of glioblastoma (GBM). To investigate plasticity-induced adaptation during standard-of-care chemotherapy temozolomide (TMZ), we performed in vivo single-cell RNA sequencing in patient-derived xenograft (PDX) tumors of GBM before, during, and after therapy. Comparing single-cell transcriptomic patterns identified distinct cellular populations present during TMZ therapy. Of interest was the increased expression of ribonucleotide reductase regulatory subunit M2 (RRM2), which we found to regulate dGTP and dCTP production vital for DNA damage response during TMZ therapy. Furthermore, multidimensional modeling of spatially resolved transcriptomic and metabolomic analysis in patients' tissues revealed strong correlations between RRM2 and dGTP. This supports our data that RRM2 regulates the demand for specific dNTPs during therapy. In addition, treatment with the RRM2 inhibitor 3-AP (Triapine) enhances the efficacy of TMZ therapy in PDX models. We present a previously unidentified understanding of chemoresistance through critical RRM2-mediated nucleotide production.
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Affiliation(s)
- Ella N. Perrault
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Jack M. Shireman
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Eunus S. Ali
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Peiyu Lin
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Isabelle Preddy
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Cheol Park
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Shreya Budhiraja
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Shivani Baisiwala
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Karan Dixit
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - C. David James
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Dieter H Heiland
- Microenvironment and Immunology Research Laboratory, Medical-Center, University of Freiburg, Freiburg, Germany
- Department of Neurosurgery, Medical-Center, University of Freiburg, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany
| | - Issam Ben-Sahra
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Sebastian Pott
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Anindita Basu
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Jason Miska
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Atique U. Ahmed
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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21
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Brown JS. Comparison of Oncogenes, Tumor Suppressors, and MicroRNAs Between Schizophrenia and Glioma: The Balance of Power. Neurosci Biobehav Rev 2023; 151:105206. [PMID: 37178944 DOI: 10.1016/j.neubiorev.2023.105206] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/25/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023]
Abstract
The risk of cancer in schizophrenia has been controversial. Confounders of the issue are cigarette smoking in schizophrenia, and antiproliferative effects of antipsychotic medications. The author has previously suggested comparison of a specific cancer like glioma to schizophrenia might help determine a more accurate relationship between cancer and schizophrenia. To accomplish this goal, the author performed three comparisons of data; the first a comparison of conventional tumor suppressors and oncogenes between schizophrenia and cancer including glioma. This comparison determined schizophrenia has both tumor-suppressive and tumor-promoting characteristics. A second, larger comparison between brain-expressed microRNAs in schizophrenia with their expression in glioma was then performed. This identified a core carcinogenic group of miRNAs in schizophrenia offset by a larger group of tumor-suppressive miRNAs. This proposed "balance of power" between oncogenes and tumor suppressors could cause neuroinflammation. This was assessed by a third comparison between schizophrenia, glioma and inflammation in asbestos-related lung cancer and mesothelioma (ALRCM). This revealed that schizophrenia shares more oncogenic similarity to ALRCM than glioma.
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22
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Moreno A, Taffet A, Tjahjono E, Anderson QL, Kirienko NV. Examining Sporadic Cancer Mutations Uncovers a Set of Genes Involved in Mitochondrial Maintenance. Genes (Basel) 2023; 14:1009. [PMID: 37239369 PMCID: PMC10218105 DOI: 10.3390/genes14051009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Mitochondria are key organelles for cellular health and metabolism and the activation of programmed cell death processes. Although pathways for regulating and re-establishing mitochondrial homeostasis have been identified over the past twenty years, the consequences of disrupting genes that regulate other cellular processes, such as division and proliferation, on affecting mitochondrial function remain unclear. In this study, we leveraged insights about increased sensitivity to mitochondrial damage in certain cancers, or genes that are frequently mutated in multiple cancer types, to compile a list of candidates for study. RNAi was used to disrupt orthologous genes in the model organism Caenorhabditis elegans, and a series of assays were used to evaluate these genes' importance for mitochondrial health. Iterative screening of ~1000 genes yielded a set of 139 genes predicted to play roles in mitochondrial maintenance or function. Bioinformatic analyses indicated that these genes are statistically interrelated. Functional validation of a sample of genes from this set indicated that disruption of each gene caused at least one phenotype consistent with mitochondrial dysfunction, including increased fragmentation of the mitochondrial network, abnormal steady-state levels of NADH or ROS, or altered oxygen consumption. Interestingly, RNAi-mediated knockdown of these genes often also exacerbated α-synuclein aggregation in a C. elegans model of Parkinson's disease. Additionally, human orthologs of the gene set showed enrichment for roles in human disorders. This gene set provides a foundation for identifying new mechanisms that support mitochondrial and cellular homeostasis.
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Affiliation(s)
| | | | | | | | - Natalia V. Kirienko
- Department of BioSciences, Rice University, 6100 Main St, MS140, Houston, TX 77005, USA; (A.M.); (A.T.); (E.T.); (Q.L.A.)
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23
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Sugur HS, Rao S, Sravya P, Athul Menon K, Arivazhagan A, Mehta B, Santosh V. IRX1 is a novel gene, overexpressed in high-grade IDH-mutant astrocytomas. Pathol Res Pract 2023; 245:154464. [PMID: 37116364 DOI: 10.1016/j.prp.2023.154464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/09/2023] [Accepted: 04/10/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND IDH-mutant astrocytomas include CNS WHO grade 2 (A2), grade 3 (A3) and grade 4 (A4), of which A3 and A4 are high-grade. A3 has a heterogenous clinical outcome that cannot be explained entirely by the existing molecular biomarkers. We comprehensively studied the transcriptome profile of A3 to determine clinical significance. METHODS TCGA mRNA-sequencing data of A3 was analyzed to derive differentially expressed genes (DEG), which were short-listed using various approaches. mRNA expression of the short-listed genes was validated using NanoString platform on a uniformly treated and molecularly characterized A3 cohort. Protein expression of one prognostically significant gene, Iroquois-class homeodomain (IRX1) was assessed by immunohistochemistry and correlated with patient survival and tumor recurrence. IRX1 expression was also studied in different grades of astrocytoma. Since DNA methyltransferase 3 alpha (DNMT3A) influences IRX1 expression, its mutations were evaluated in a subset of tumors. RESULTS TCGA analysis identified 96 DEG in A3 tumours. 57 genes were short-listed and finally narrowed down to 14 genes. mRNA values of 12/14 genes validated in our cohort. On multiple-variable analysis, IRX1 was the most prognostically relevant gene, with respect to progression free survival of patients. Further, IRX1 immunoexpression was significantly higher in A3 and A4 when compared to A2 and glioblastoma. Higher IRX1 immunoexpression correlated with poor prognosis in patients with A3 tumours. Also, a higher IRX1 expression was associated with DNMT3A mutation. CONCLUSION Our study identifies IRX1 as a novel biomarker overexpressed in high-grade IDH-mutant astrocytomas with prognostic significance in A3. DNMT3A mutation probably modulates IRX1 expression.
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Affiliation(s)
- Harsha S Sugur
- Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka 560029, India
| | - Shilpa Rao
- Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka 560029, India
| | - Palavalasa Sravya
- Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka 560029, India
| | - K Athul Menon
- Theracues Innovations Pvt. Ltd, Sahakar Nagar, Bangalore, Karnataka 560092, India
| | - Arimappamagan Arivazhagan
- Department of Neurosurgery, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Bhupesh Mehta
- Department of Biophysics, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka 560029, India
| | - Vani Santosh
- Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka 560029, India.
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24
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Peng P, Chen ZR, Zhang XL, Guo DS, Zhang B, He XM, Wan F. Construction and Verification of an RNA-Binding Protein-Associated Prognostic Model for Gliomas. Curr Med Sci 2023; 43:156-165. [PMID: 36867360 DOI: 10.1007/s11596-022-2694-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 09/29/2021] [Indexed: 03/04/2023]
Abstract
OBJECTIVE To construct and verificate an RNA-binding protein (RBP)-associated prognostic model for gliomas using integrated bioinformatics analysis. METHODS RNA-sequencing and clinic pathological data of glioma patients from The Cancer Genome Atlas (TCGA) database and the Chinese Glioma Genome Atlas database (CGGA) were downloaded. The aberrantly expressed RBPs were investigated between gliomas and normal samples in TCGA database. We then identified prognosis related hub genes and constructed a prognostic model. This model was further validated in the CGGA-693 and CGGA-325 cohorts. RESULTS Totally 174 differently expressed genes-encoded RBPs were identified, containing 85 down-regulated and 89 up-regulated genes. We identified five genes-encoded RBPs (ERI1, RPS2, BRCA1, NXT1, and TRIM21) as prognosis related key genes and constructed a prognostic model. Overall survival (OS) analysis revealed that the patients in the high-risk subgroup based on the model were worse than those in the low-risk subgroup. The area under the receiver operator characteristic curve (AUC) of the prognostic model was 0.836 in the TCGA dataset and 0.708 in the CGGA-693 dataset, demonstrating a favorable prognostic model. Survival analyses of the five RBPs in the CGGA-325 cohort validated the findings. A nomogram was constructed based on the five genes and validated in the TCGA cohort, confirming a promising discriminating ability for gliomas. CONCLUSION The prognostic model of the five RBPs might serve as an independent prognostic algorithm for gliomas.
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Affiliation(s)
- Peng Peng
- Department of Neurosurgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, 441021, China
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zi-Rong Chen
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiao-Lin Zhang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dong-Sheng Guo
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bin Zhang
- Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xi-Miao He
- Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Feng Wan
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
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25
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Khan P, Siddiqui JA, Kshirsagar PG, Venkata RC, Maurya SK, Mirzapoiazova T, Perumal N, Chaudhary S, Kanchan RK, Fatima M, Khan MA, Rehman AU, Lakshmanan I, Mahapatra S, Talmon GA, Kulkarni P, Ganti AK, Jain M, Salgia R, Batra SK, Nasser MW. MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis. Mol Cancer 2023; 22:1. [PMID: 36597126 PMCID: PMC9811802 DOI: 10.1186/s12943-022-01695-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 12/06/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood. METHODS To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, identified miRNA) in patient serum samples and SCLC cell lines. To assess the therapeutic potential of miR-1, we developed various in vitro models, including miR-1 sponge (miR-1Zip) and DOX-On-miR-1 (Tet-ON) inducible stable overexpression systems. Mouse models derived from intracardiac injection of SCLC cells (miR-1Zip and DOX-On-miR-1) were established to delineate the role of miR-1 in SCLC metastasis. In situ hybridization and immunohistochemistry were used to analyze the expression of miR-1 and target proteins (mouse and human tumor specimens), respectively. Dual-luciferase assay was used to validate the target of miR-1, and chromatin immunoprecipitation assay was used to investigate the protein-gene interactions. RESULTS A consistent downregulation of miR-1 was observed in tumor tissues and serum samples of SCLC patients compared to their matched normal controls, and these results were recapitulated in SCLC cell lines. Gain of function studies of miR-1 in SCLC cell lines showed decreased cell growth and oncogenic signaling, whereas loss of function studies of miR-1 rescued this effect. Intracardiac injection of gain of function of miR-1 SCLC cell lines in the mouse models showed a decrease in distant organ metastasis, whereas loss of function of miR-1 potentiated growth and metastasis. Mechanistic studies revealed that CXCR4 is a direct target of miR-1 in SCLC. Using unbiased transcriptomic analysis, we identified CXCR4/FOXM1/RRM2 as a unique axis that regulates SCLC growth and metastasis. Our results further showed that FOXM1 directly binds to the RRM2 promoter and regulates its activity in SCLC. CONCLUSIONS Our findings revealed that miR-1 is a critical regulator for decreasing SCLC growth and metastasis. It targets the CXCR4/FOXM1/RRM2 axis and has a high potential for the development of novel SCLC therapies. MicroRNA-1 (miR-1) downregulation in the tumor tissues and serum samples of SCLC patients is an important hallmark of tumor growth and metastasis. The introduction of miR-1 in SCLC cell lines decreases cell growth and metastasis. Mechanistically, miR-1 directly targets CXCR4, which further prevents FOXM1 binding to the RRM2 promoter and decreases SCLC growth and metastasis.
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Affiliation(s)
- Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Prakash G Kshirsagar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | | | - Shailendra Kumar Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Tamara Mirzapoiazova
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA
| | - Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana Kumari Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mahek Fatima
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Md Arafat Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Asad Ur Rehman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Prakash Kulkarni
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA
| | - Apar K Ganti
- Division of Oncology-Hematology, Department of Internal Medicine, VA-Nebraska Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, 91010, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Li X, Wang N, Leng H, Yuan H, Xu L. Hsa_circ_0043949 reinforces temozolomide resistance via upregulating oncogene ITGA1 axis in glioblastoma. Metab Brain Dis 2022; 37:2979-2993. [PMID: 36301458 DOI: 10.1007/s11011-022-01069-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/08/2022] [Indexed: 10/31/2022]
Abstract
Temozolomide (TMZ) resistance limits its use in glioblastoma (GBM). Exosomes can carry circular RNAs (circRNAs) to regulate chemoresistance. To date, the role of exosomal hsa_circ_0043949 (circ_0043949) in GBM resistance to TMZ is unclear. Relative expression of circ_0043949 in clinical samples, GBM cell lines, and exosomes was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The half-maximal inhibitory concentration (IC50) of TMZ, cell proliferation, apoptosis, invasion, and migration were analyzed via MTT, EdU, flow cytometry, transwell, and wound-healing assays. Relative protein levels were evaluated by western blotting. Target relationship was predicted by bioinformatics analysis and validated by dual-luciferase reporter and RNA pull-down assays. Exosomes were isolated by ultracentrifugation and verified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The effect of exosomal circ_0043949 on TMZ resistance was validated by xenograft assay. Higher expression of circ_0043949 was gained in TMZ-resistant GBM samples and cells. Inhibition of circ_0043949 reduced TMZ resistance via decreasing IC50 of TMZ, repressing proliferation, invasion, migration, and inducing apoptosis in TMZ-resistant GBM cells. Circ_0043949 mediated integrinalpha1 (ITGA1) expression via function as a miR-876-3p sponge. Circ_0043949 was also upregulated in TMZ-resistant GBM cells-derived exosomes, and exosomal circ_0043949 increased the resistance of TMZ-resistant GBM cells to TMZ in xenograft models. TMZ-resistant GBM cells-derived exosomal circ_0043949 promoted TMZ resistance via upregulating ITGA1 expression via sequestering miR-876-3p, offering a potential target for the treatment of TMZ resistance in GBM.
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Affiliation(s)
- Xuzhao Li
- Department of Neurosurgery, The First People's Hospital of Changde City, Changde City, 415000, Hunan, China
| | - Nianhua Wang
- Department of Neurosurgery, The First People's Hospital of Changde City, Changde City, 415000, Hunan, China
| | - Haibin Leng
- Department of Neurosurgery, The First People's Hospital of Changde City, Changde City, 415000, Hunan, China
| | - Huichun Yuan
- Department of Neurosurgery, The First People's Hospital of Changde City, Changde City, 415000, Hunan, China
| | - Lixin Xu
- Department of Neurosurgery, The First People's Hospital of Changde City, Changde City, 415000, Hunan, China.
- Department of Neurosurgery, The First People's Hospital of Changde City, No.818, Renmin Road, Changde, 415000, Hunan, China.
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Lai G, Zhong X, Liu H, Deng J, Li K, Xie B. Development of a Hallmark Pathway-Related Gene Signature Associated with Immune Response for Lower Grade Gliomas. Int J Mol Sci 2022; 23:ijms231911971. [PMID: 36233273 PMCID: PMC9570050 DOI: 10.3390/ijms231911971] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/04/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022] Open
Abstract
Although some biomarkers have been used to predict prognosis of lower-grade gliomas (LGGs), a pathway-related signature associated with immune response has not been developed. A key signaling pathway was determined according to the lowest adjusted p value among 50 hallmark pathways. The least absolute shrinkage and selection operator (LASSO) and stepwise multivariate Cox analyses were performed to construct a pathway-related gene signature. Somatic mutation, drug sensitivity and prediction of immunotherapy analyses were conducted to reveal the value of this signature in targeted therapies. In this study, an allograft rejection (AR) pathway was considered as a crucial signaling pathway, and we constructed an AR-related five-gene signature, which can independently predict the prognosis of LGGs. High-AR LGG patients had higher tumor mutation burden (TMB), Immunophenscore (IPS), IMmuno-PREdictive Score (IMPRES), T cell-inflamed gene expression profile (GEP) score and MHC I association immunoscore (MIAS) than low-AR patients. Most importantly, our signature can be validated in four immunotherapy cohorts. Furthermore, IC50 values of the six classic chemotherapeutic drugs were significantly elevated in the low-AR group compared with the high-AR group. This signature might be regarded as an underlying biomarker in predicting prognosis for LGGs, possibly providing more therapeutic strategies for future clinical research.
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Lin W, Wang Q, Chen Y, Wang N, Ni Q, Qi C, Wang Q, Zhu Y. Identification of a 6-RBP gene signature for a comprehensive analysis of glioma and ischemic stroke: Cognitive impairment and aging-related hypoxic stress. Front Aging Neurosci 2022; 14:951197. [PMID: 36118697 PMCID: PMC9476601 DOI: 10.3389/fnagi.2022.951197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
There is mounting evidence that ischemic cerebral infarction contributes to vascular cognitive impairment and dementia in elderly. Ischemic stroke and glioma are two majorly fatal diseases worldwide, which promote each other's development based on some common underlying mechanisms. As a post-transcriptional regulatory protein, RNA-binding protein is important in the development of a tumor and ischemic stroke (IS). The purpose of this study was to search for a group of RNA-binding protein (RBP) gene markers related to the prognosis of glioma and the occurrence of IS, and elucidate their underlying mechanisms in glioma and IS. First, a 6-RBP (POLR2F, DYNC1H1, SMAD9, TRIM21, BRCA1, and ERI1) gene signature (RBPS) showing an independent overall survival prognostic prediction was identified using the transcriptome data from TCGA-glioma cohort (n = 677); following which, it was independently verified in the CGGA-glioma cohort (n = 970). A nomogram, including RBPS, 1p19q codeletion, radiotherapy, chemotherapy, grade, and age, was established to predict the overall survival of patients with glioma, convenient for further clinical transformation. In addition, an automatic machine learning classification model based on radiomics features from MRI was developed to stratify according to the RBPS risk. The RBPS was associated with immunosuppression, energy metabolism, and tumor growth of gliomas. Subsequently, the six RBP genes from blood samples showed good classification performance for IS diagnosis (AUC = 0.95, 95% CI: 0.902–0.997). The RBPS was associated with hypoxic responses, angiogenesis, and increased coagulation in IS. Upregulation of SMAD9 was associated with dementia, while downregulation of POLR2F was associated with aging-related hypoxic stress. Irf5/Trim21 in microglia and Taf7/Trim21 in pericytes from the mouse cerebral cortex were identified as RBPS-related molecules in each cell type under hypoxic conditions. The RBPS is expected to serve as a novel biomarker for studying the common mechanisms underlying glioma and IS.
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Affiliation(s)
- Weiwei Lin
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang, Hangzhou, China
| | - Qiangwei Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang, Hangzhou, China
| | - Yisheng Chen
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning Wang
- Brain Center, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingbin Ni
- Postdoctoral Workstation, Department of Central Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
| | - Chunhua Qi
- Postdoctoral Workstation, Department of Central Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
| | - Qian Wang
- Postdoctoral Workstation, Department of Central Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
- *Correspondence: Qian Wang
| | - Yongjian Zhu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases of Zhejiang, Hangzhou, China
- College of Mathematical Medicine, Zhejiang Normal University, Jinhua, China
- Yongjian Zhu
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29
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Nunes C, Depestel L, Mus L, Keller KM, Delhaye L, Louwagie A, Rishfi M, Whale A, Kara N, Andrews SR, Dela Cruz F, You D, Siddiquee A, Cologna CT, De Craemer S, Dolman E, Bartenhagen C, De Vloed F, Sanders E, Eggermont A, Bekaert SL, Van Loocke W, Bek JW, Dewyn G, Loontiens S, Van Isterdael G, Decaesteker B, Tilleman L, Van Nieuwerburgh F, Vermeirssen V, Van Neste C, Ghesquiere B, Goossens S, Eyckerman S, De Preter K, Fischer M, Houseley J, Molenaar J, De Wilde B, Roberts SS, Durinck K, Speleman F. RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition. SCIENCE ADVANCES 2022; 8:eabn1382. [PMID: 35857500 PMCID: PMC9278860 DOI: 10.1126/sciadv.abn1382] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 05/26/2022] [Indexed: 05/06/2023]
Abstract
High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.
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Affiliation(s)
- Carolina Nunes
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Lisa Depestel
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Liselot Mus
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | | | - Louis Delhaye
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- VIB-UGent Center for Medical Biotechnology, Ghent University, Ghent, Belgium
| | - Amber Louwagie
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Muhammad Rishfi
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Alex Whale
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | - Neesha Kara
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | | | - Filemon Dela Cruz
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Daoqi You
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Armaan Siddiquee
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Camila Takeno Cologna
- Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Sam De Craemer
- Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Emmy Dolman
- Princess Maxima Center, Utrecht, Netherlands
| | - Christoph Bartenhagen
- Center for Molecular Medicine Cologne, Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
- Department of Experimental Pediatric Oncology, University Children’s Hospital of Cologne, Cologne, Germany
| | - Fanny De Vloed
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Ellen Sanders
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Aline Eggermont
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Sarah-Lee Bekaert
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Wouter Van Loocke
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Jan Willem Bek
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Givani Dewyn
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Siebe Loontiens
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | | | - Bieke Decaesteker
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Laurentijn Tilleman
- NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | | | - Vanessa Vermeirssen
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Christophe Van Neste
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Bart Ghesquiere
- Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Steven Goossens
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Sven Eyckerman
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
- VIB-UGent Center for Medical Biotechnology, Ghent University, Ghent, Belgium
| | - Katleen De Preter
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Matthias Fischer
- Center for Molecular Medicine Cologne, Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
- Department of Experimental Pediatric Oncology, University Children’s Hospital of Cologne, Cologne, Germany
| | - Jon Houseley
- Epigenetics Programme, Babraham Institute, Cambridge, UK
| | | | - Bram De Wilde
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Stephen S. Roberts
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kaat Durinck
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Frank Speleman
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
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Targeting matrix metallopeptidase 2 by hydroxyurea selectively kills acute myeloid mixed-lineage leukemia. Cell Death Dis 2022; 8:180. [PMID: 35396375 PMCID: PMC8993889 DOI: 10.1038/s41420-022-00989-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/02/2022] [Accepted: 03/21/2022] [Indexed: 12/02/2022]
Abstract
Oncogene-induced tumorigenesis results in the variation of epigenetic modifications, and in addition to promoting cell immortalization, cancer cells undergo more intense cellular stress than normal cells and depend on other support genes for survival. Chromosomal translocations of mixed-lineage leukemia (MLL) induce aggressive leukemias with an inferior prognosis. Unfortunately, most MLL-rearranged (MLL-r) leukemias are resistant to conventional chemotherapies. Here, we showed that hydroxyurea (HU) could kill MLL-r acute myeloid leukemia (AML) cells through the necroptosis process. HU target these cells by matrix metallopeptidase 2 (MMP2) deficiency rather than subordinate ribonucleotide reductase regulatory subunit M2 (RRM2) inhibition, where MLL directly regulates MMP2 expression and is decreased in most MLL-r AMLs. Moreover, iron chelation of HU is also indispensable for inducing cell stress, and MMP2 is the support factor to protect cells from death. Our preliminary study indicates that MMP2 might play a role in the nonsense-mediated mRNA decay pathway that prevents activation of unfolding protein response under innocuous endoplasmic reticulum stress. Hence, these results reveal a possible strategy of HU application in MLL-r AML treatment and shed new light upon HU repurposing.
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Shan J, Wang Z, Mo Q, Long J, Fan Y, Cheng L, Zhang T, Liu X, Wang X. Ribonucleotide reductase M2 subunit silencing suppresses tumorigenesis in pancreatic cancer via inactivation of PI3K/AKT/mTOR pathway. Pancreatology 2022; 22:401-413. [PMID: 35300916 DOI: 10.1016/j.pan.2022.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/26/2022] [Accepted: 03/02/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Ribonucleotide Reductase M2 subunit (RRM2) is elevated in pancreatic cancer and involved in DNA synthesis and cell proliferation. But its specific mechanism including genetic differences and upstream regulatory pathways remains unclear. METHODS We analyzed RRM2 expression of 178 pancreatic cancer patients in Gene Expression Profiling Interactive Analysis (GEPIA) database. Besides, more pancreatic cancer specimens were collected and detected RRM2 expression by immunohistochemistry. RRM2 knockdown by shRNA was applied for functional and mechanism analysis in vitro. Xenograft tumor growth was significantly slower by RRM2 silencing in vivo. RESULTS It showed that high RRM2 expression had a poorer overall survival and disease free survival. RRM2 expression was higher in tumor grade 2 and 3 than grade 1. Immunohistochemistry data validated that high RRM2 expression predicted worse survival. RRM2 knockdown significantly reduced cell proliferation, inhibited colony formation and suppressed cell cycle progress. Further mechanism assay showed silencing RRM2 lead to inactivation of PI3K/AKT/mTOR pathway and inhibition of mutant p53, which induce S phase arrest and/or apoptosis. In panc-1 cells, S-phase arrest mediated by mutant p53 inhibition, p21 increase and cell cycle related proteins change. While in miapaca-2 cells, induction of apoptosis and S-phase arrest mediated by CDK1 played a coordinated role. CONCLUSION Taken together, high RRM2 expression was associated with worse prognosis. Importantly, RRM2 knockdown deactivated PI3K/AKT/mTOR pathway, resulting in cell cycle arrest and/or apoptosis. This study shed light on the molecular mechanism of RRM2 in pancreatic tumor progression and is expected to provide a new theoretical basis for pancreatic cancer treatment.
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Affiliation(s)
- Jinlan Shan
- Department of Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Department of Cancer Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhen Wang
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qiuping Mo
- Department of Breast Surgery, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, China
| | - Jingpei Long
- Department of Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yangfan Fan
- Department of Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lu Cheng
- Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Tao Zhang
- Department of Breast and Thyroid Surgery, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Xiyong Liu
- Sino-America Cancer Foundation, California Cancer Institute, Temple City, CA91780, USA; Tumor Biomarker Development, California Cancer Institute, Temple City, CA,91780, USA
| | - Xiaochen Wang
- Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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32
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RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway. Biomolecules 2022; 12:biom12020299. [PMID: 35204799 PMCID: PMC8869767 DOI: 10.3390/biom12020299] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/06/2022] [Accepted: 02/07/2022] [Indexed: 02/04/2023] Open
Abstract
Doxorubicin (DOX) is an effective chemotherapeutic agent that plays an unparalleled role in cancer treatment. However, its serious dose-dependent cardiotoxicity, which eventually contributes to irreversible heart failure, has greatly limited the widespread clinical application of DOX. A previous study has demonstrated that the ribonucleotide reductase M2 subunit (RRM2) exerts salutary effects on promoting proliferation and inhibiting apoptosis and autophagy. However, the specific function of RRM2 in DOX-induced cardiotoxicity is yet to be determined. This study aimed to elucidate the role and potential mechanism of RRM2 on DOX-induced cardiotoxicity by investigating neonatal primary cardiomyocytes and mice treated with DOX. Subsequently, the results indicated that RRM2 expression was significantly reduced in mice hearts and primary cardiomyocytes. Apoptosis and autophagy-related proteins, such as cleaved-Caspase3 (C-Caspase3), LC3B, and beclin1, were distinctly upregulated. Additionally, RRM2 deficiency led to increased autophagy and apoptosis in cells. RRM2 overexpression, on the contrary, alleviated DOX-induced cardiotoxicity in vivo and in vitro. Consistently, DIDOX, an inhibitor of RRM2, attenuated the protective effect of RRM2. Mechanistically, we found that AKT/mTOR inhibitors could reverse the function of RRM2 overexpression on DOX-induced autophagy and apoptosis, which means that RRM2 could have regulated DOX-induced cardiotoxicity through the AKT/mTOR signaling pathway. In conclusion, our experiment established that RRM2 could be a potential treatment in reversing DOX-induced cardiac dysfunction.
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33
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Long MJC, Ly P, Aye Y. Still no Rest for the Reductases: Ribonucleotide Reductase (RNR) Structure and Function: An Update. Subcell Biochem 2022; 99:155-197. [PMID: 36151376 DOI: 10.1007/978-3-031-00793-4_5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Herein we present a multidisciplinary discussion of ribonucleotide reductase (RNR), the essential enzyme uniquely responsible for conversion of ribonucleotides to deoxyribonucleotides. This chapter primarily presents an overview of this multifaceted and complex enzyme, covering RNR's role in enzymology, biochemistry, medicinal chemistry, and cell biology. It further focuses on RNR from mammals, whose interesting and often conflicting roles in health and disease are coming more into focus. We present pitfalls that we think have not always been dealt with by researchers in each area and further seek to unite some of the field-specific observations surrounding this enzyme. Our work is thus not intended to cover any one topic in extreme detail, but rather give what we consider to be the necessary broad grounding to understand this critical enzyme holistically. Although this is an approach we have advocated in many different areas of scientific research, there is arguably no other single enzyme that embodies the need for such broad study than RNR. Thus, we submit that RNR itself is a paradigm of interdisciplinary research that is of interest from the perspective of the generalist and the specialist alike. We hope that the discussions herein will thus be helpful to not only those wanting to tackle RNR-specific problems, but also those working on similar interdisciplinary projects centering around other enzymes.
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Affiliation(s)
- Marcus J C Long
- University of Lausanne (UNIL), Lausanne, Switzerland
- Department of Biochemistry, UNIL, Epalinges, Switzerland
| | - Phillippe Ly
- Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
- EPFL SB ISIC LEAGO, Lausanne, Switzerland
| | - Yimon Aye
- Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
- EPFL SB ISIC LEAGO, Lausanne, Switzerland.
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34
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Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas. Cancers (Basel) 2021; 13:cancers13225678. [PMID: 34830833 PMCID: PMC8616465 DOI: 10.3390/cancers13225678] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, due in great part to treatment resistance driven by complex DNA repair mechanisms. pHGGs have recently been divided into molecular subtypes based on mutations affecting the N-terminal tail of the histone variant H3.3 and the ATRX/DAXX histone chaperone that deposits H3.3 at repetitive heterochromatin loci that are of paramount importance to the stability of our genome. This review addresses the functions of H3.3 and ATRX/DAXX in chromatin dynamics and DNA repair, as well as the impact of mutations affecting H3.3/ATRX/DAXX on treatment resistance and how the vulnerabilities they expose could foster novel therapeutic strategies. Abstract Despite their low incidence, pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine gliomas (DIPGs), are the leading cause of mortality in pediatric neuro-oncology. Recurrent, mutually exclusive mutations affecting K27 (K27M) and G34 (G34R/V) in the N-terminal tail of histones H3.3 and H3.1 act as key biological drivers of pHGGs. Notably, mutations in H3.3 are frequently associated with mutations affecting ATRX and DAXX, which encode a chaperone complex that deposits H3.3 into heterochromatic regions, including telomeres. The K27M and G34R/V mutations lead to distinct epigenetic reprogramming, telomere maintenance mechanisms, and oncogenesis scenarios, resulting in distinct subgroups of patients characterized by differences in tumor localization, clinical outcome, as well as concurrent epigenetic and genetic alterations. Contrasting with our understanding of the molecular biology of pHGGs, there has been little improvement in the treatment of pHGGs, with the current mainstays of therapy—genotoxic chemotherapy and ionizing radiation (IR)—facing the development of tumor resistance driven by complex DNA repair pathways. Chromatin and nucleosome dynamics constitute important modulators of the DNA damage response (DDR). Here, we summarize the major DNA repair pathways that contribute to resistance to current DNA damaging agent-based therapeutic strategies and describe the telomere maintenance mechanisms encountered in pHGGs. We then review the functions of H3.3 and its chaperones in chromatin dynamics and DNA repair, as well as examining the impact of their mutation/alteration on these processes. Finally, we discuss potential strategies targeting DNA repair and epigenetic mechanisms as well as telomere maintenance mechanisms, to improve the treatment of pHGGs.
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Vengoji R, Atri P, Macha MA, Seshacharyulu P, Perumal N, Mallya K, Liu Y, Smith LM, Rachagani S, Mahapatra S, Ponnusamy MP, Jain M, Batra SK, Shonka N. Differential gene expression-based connectivity mapping identified novel drug candidate and improved Temozolomide efficacy for Glioblastoma. J Exp Clin Cancer Res 2021; 40:335. [PMID: 34696786 PMCID: PMC8543939 DOI: 10.1186/s13046-021-02135-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 10/08/2021] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment. METHODS We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM's specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability. RESULTS We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTENflox/+; EGFRvIII+; p16Flox/- & GFAP Cre +). PCI-24781 significantly inhibited tumor growth and downregulated DNA repair machinery (BRCA1, CHK1, RAD51, and O6-methylguanine-DNA- methyltransferase (MGMT)), increasing DNA double-strand breaks and causing apoptosis in the GBM cell lines, including an MGMT expressing cell line in vitro. Further, PCI-24781 decreased tumor burden in a PEPG GBM mouse model. Notably, TMZ + PCI increased survival in orthotopic murine models compared to TMZ + vorinostat, a pan-HDAC inhibitor that proved unsuccessful in clinical trials. CONCLUSION PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation.
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Affiliation(s)
- Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Jammu & Kashmir, India
| | - Parthasarathy Seshacharyulu
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Kavita Mallya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Yutong Liu
- Department of Radiology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Lynette M Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
| | - Nicole Shonka
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA.
- Department of Internal Medicine, Division of Oncology & Hematology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Lozinski M, Bowden NA, Graves MC, Fay M, Tooney PA. DNA damage repair in glioblastoma: current perspectives on its role in tumour progression, treatment resistance and PIKKing potential therapeutic targets. Cell Oncol (Dordr) 2021; 44:961-981. [PMID: 34057732 DOI: 10.1007/s13402-021-00613-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 05/17/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The aggressive, invasive and treatment resistant nature of glioblastoma makes it one of the most lethal cancers in humans. Total surgical resection is difficult, and a combination of radiation and chemotherapy is used to treat the remaining invasive cells beyond the tumour border by inducing DNA damage and activating cell death pathways in glioblastoma cells. Unfortunately, recurrence is common and a major hurdle in treatment, often met with a more aggressive and treatment resistant tumour. A mechanism of resistance is the response of DNA repair pathways upon treatment-induced DNA damage, which enact cell-cycle arrest and repair of DNA damage that would otherwise cause cell death in tumour cells. CONCLUSIONS In this review, we discuss the significance of DNA repair mechanisms in tumour formation, aggression and treatment resistance. We identify an underlying trend in the literature, wherein alterations in DNA repair pathways facilitate glioma progression, while established high-grade gliomas benefit from constitutively active DNA repair pathways in the repair of treatment-induced DNA damage. We also consider the clinical feasibility of inhibiting DNA repair in glioblastoma and current strategies of using DNA repair inhibitors as agents in combination with chemotherapy, radiation or immunotherapy. Finally, the importance of blood-brain barrier penetrance when designing novel small-molecule inhibitors is discussed.
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Affiliation(s)
- Mathew Lozinski
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia
- Centre for Drug Repurposing and Medicines Research, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Nikola A Bowden
- Centre for Drug Repurposing and Medicines Research, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Newcastle, NSW, Australia
- School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia
| | - Moira C Graves
- Centre for Drug Repurposing and Medicines Research, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Newcastle, NSW, Australia
- School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia
| | - Michael Fay
- Centre for Drug Repurposing and Medicines Research, University of Newcastle, Newcastle, NSW, Australia
- Hunter Medical Research Institute, Newcastle, NSW, Australia
- Genesis Cancer Care, Gateshead, New South Wales, Australia
| | - Paul A Tooney
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, NSW, Australia.
- Centre for Drug Repurposing and Medicines Research, University of Newcastle, Newcastle, NSW, Australia.
- Hunter Medical Research Institute, Newcastle, NSW, Australia.
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Meimand SE, Pour-Rashidi A, Shahrbabak MM, Mohammadi E, Meimand FE, Rezaei N. The Prognostication Potential of BRCA Genes Expression in Gliomas: A Genetic Survival Analysis Study. World Neurosurg 2021; 157:e123-e128. [PMID: 34607064 DOI: 10.1016/j.wneu.2021.09.107] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gliomas are the most common type of central nervous system tumor in adults, and they have an extremely poor prognosis. Gliomas are classified into 4 grades, with low-grade gliomas (LGGs) constituting grades I and II and glioblastoma multiforme (GBM) constituting grade IV. Breast cancer susceptibility genes BRCA1 and BRCA2 play a role in DNA repair and are required for genome stability. METHODS We analyzed the LGG and GBM cohorts from The Cancer Genome Atlas. We used Kaplan-Meier and log-rank analysis to determine the relationship between BRCA1 and BRCA2 expression and survival. RESULTS Correlation of BRCA1 and BRCA2 expression with survival in patients with LGG was significant (P = 0.00 and P = 0.00). The higher the levels of expression were, the lower survival rates were in both LGG and GBM cohorts, but the correlation was not significant in patients with GBM (P < 0.01). CONCLUSIONS Our findings suggest that BRCA1 and BRCA2 can be regarded as poor prognostic factors in patients with glioma, with greater significance in patients with LGG. In the future, more in-depth experiments will enable us to elucidate the mechanism of gliomagenesis and identify potential gene therapy targets.
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Affiliation(s)
- Sepideh Ebrahimi Meimand
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Pour-Rashidi
- Department of Neurosurgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Esmaeil Mohammadi
- Department of Pediatric Neurosurgery, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Sina Trauma and Surgery Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Nima Rezaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran.
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Xu S, Wang Z, Ye J, Mei S, Zhang J. Identification of Iron Metabolism-Related Genes as Prognostic Indicators for Lower-Grade Glioma. Front Oncol 2021; 11:729103. [PMID: 34568059 PMCID: PMC8458946 DOI: 10.3389/fonc.2021.729103] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/23/2021] [Indexed: 12/13/2022] Open
Abstract
Lower-grade glioma (LGG) is characterized by genetic and transcriptional heterogeneity, and a dismal prognosis. Iron metabolism is considered central for glioma tumorigenesis, tumor progression and tumor microenvironment, although key iron metabolism-related genes are unclear. Here we developed and validated an iron metabolism-related gene signature LGG prognosis. RNA-sequence and clinicopathological data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were downloaded. Prognostic iron metabolism-related genes were screened and used to construct a risk-score model via differential gene expression analysis, univariate Cox analysis, and the Least Absolute Shrinkage and Selection Operator (LASSO)-regression algorithm. All LGG patients were stratified into high- and low-risk groups, based on the risk score. The prognostic significance of the risk-score model in the TCGA and CGGA cohorts was evaluated with Kaplan-Meier (KM) survival and receiver operating characteristic (ROC) curve analysis. Risk- score distributions in subgroups were stratified by age, gender, the World Health Organization (WHO) grade, isocitrate dehydrogenase 1 (IDH1) mutation status, the O6-methylguanine-DNA methyl-transferase (MGMT) promoter-methylation status, and the 1p/19q co-deletion status. Furthermore, a nomogram model with a risk score was developed, and its predictive performance was validated with the TCGA and CGGA cohorts. Additionally, the gene set enrichment analysis (GSEA) identified signaling pathways and pathological processes enriched in the high-risk group. Finally, immune infiltration and immune checkpoint analysis were utilized to investigate the tumor microenvironment characteristics related to the risk score. We identified a prognostic 15-gene iron metabolism-related signature and constructed a risk-score model. High risk scores were associated with an age of > 40, wild-type IDH1, a WHO grade of III, an unmethylated MGMT promoter, and 1p/19q non-codeletion. ROC analysis indicated that the risk-score model accurately predicted 1-, 3-, and 5-year overall survival rates of LGG patients in the both TCGA and CGGA cohorts. KM analysis showed that the high-risk group had a much lower overall survival than the low-risk group (P < 0.0001). The nomogram model showed a strong ability to predict the overall survival of LGG patients in the TCGA and CGGA cohorts. GSEA analysis indicated that inflammatory responses, tumor-associated pathways, and pathological processes were enriched in high-risk group. Moreover, a high risk score correlated with the infiltration immune cells (dendritic cells, macrophages, CD4+ T cells, and B cells) and expression of immune checkpoint (PD1, PDL1, TIM3, and CD48). Our prognostic model was based on iron metabolism-related genes in LGG, can potentially aid in LGG prognosis, and provides potential targets against gliomas.
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Affiliation(s)
- Shenbin Xu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
- Department of Gastroenterology Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zefeng Wang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Juan Ye
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Shuhao Mei
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianmin Zhang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Brain Research Institute, Zhejiang University, Hangzhou, China
- Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, China
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Chen Z, Wu H, Yang H, Fan Y, Zhao S, Zhang M. Identification and validation of RNA-binding protein-related gene signature revealed potential associations with immunosuppression and drug sensitivity in glioma. Cancer Med 2021; 10:7418-7439. [PMID: 34482648 PMCID: PMC8525098 DOI: 10.1002/cam4.4248] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/31/2021] [Accepted: 08/22/2021] [Indexed: 12/11/2022] Open
Abstract
Background Glioma is the most common central nervous system tumor in adults, and a considerable part of them are high‐degree ones with high malignancy and poor prognosis. At present, the classification and treatment of glioma are mainly based on its histological characteristics, so studies at the molecular level are needed. Methods RNA‐seq data from The Cancer Genome Atlas (TCGA) datasets (n = 703) and Chinese Glioma Genome Atlas (CGGA) were utilized to find out the differentially expressed RNA‐binding proteins (RBPs) between normal cerebral tissue and glioma. A prediction system for the prognosis of glioma patients based on 11 RBPs was established and validated using uni‐ and multi‐variate Cox regression analyses. STITCH and CMap databases were exploited to identify putative drugs and their targets. Single sample gene set enrichment analysis (ssGSEA) was used to calculate scores of specific immune‐related gene sets. IC50 of over 20,000 compounds in 60 cancer cell lines was collected from the CellMiner database to test the drug sensitivity prediction value of the RBP‐based signature. Results We established a reliable prediction system for the prognosis of glioma patients based on 11 RBPs including THOC3, LSM11, SARNP, PABPC1L2B, SMN1, BRCA1, ZC3H8, DZIP1L, HEXIM2, LARP4B, and ZC3H12B. These RBPs were primarily associated with ribosome and post‐transcriptional regulation. RBP‐based risk scores were closely related to immune cells and immune function. We also confirmed the potential of the signature to predict the drug sensitivity of currently approved or evaluated drugs. Conclusions Differentially expressed RBPs in glioma can be used as a basis for prognosis prediction, new drugs screening and drug sensitivity prediction. As RBP‐based glioma risk scores were associated with immunity, immunotherapy may become an important treatment for glioma in the future.
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Affiliation(s)
- Zhuohui Chen
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Haiyue Wu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Haojun Yang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Yishu Fan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Songfeng Zhao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Mengqi Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
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Liu Q, Guo L, Qi H, Lou M, Wang R, Hai B, Xu K, Zhu L, Ding Y, Li C, Xie L, Shen J, Xiang X, Shao J. A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer. Cell Death Dis 2021; 12:683. [PMID: 34234118 PMCID: PMC8263627 DOI: 10.1038/s41419-021-03969-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/22/2021] [Accepted: 06/23/2021] [Indexed: 12/22/2022]
Abstract
Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.
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Affiliation(s)
- Qian Liu
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lijuan Guo
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongyan Qi
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University Cancer Center, Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China
| | - Meng Lou
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University Cancer Center, Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China
| | - Rui Wang
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Boning Hai
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kailun Xu
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University Cancer Center, Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China
| | - Lijun Zhu
- Key Laboratory of Pancreatic Disease of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongfeng Ding
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Pancreatic Disease of Zhejiang Province, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chen Li
- Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingdan Xie
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University Cancer Center, Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Shen
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University Cancer Center, Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China
| | - Xueping Xiang
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Zhejiang University Cancer Center, Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China.
| | - Jimin Shao
- Department of Pathology & Pathophysiology, and Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Zhejiang University Cancer Center, Key Laboratory of Disease Proteomics of Zhejiang Province, Key Laboratory of Cancer Prevention and Intervention of China National Ministry of Education, Zhejiang University School of Medicine, Hangzhou, China.
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Cui Y, Yang Z, Wang H, Yan Y, Huang Q, Gong Z, Hong F, Zhang X, Li W, Chen J, Xu T. Identification of CDKL3 as a critical regulator in development of glioma through regulating RRM2 and the JNK signaling pathway. Cancer Sci 2021; 112:3150-3162. [PMID: 34097336 PMCID: PMC8353949 DOI: 10.1111/cas.15010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 06/01/2021] [Accepted: 06/03/2021] [Indexed: 12/12/2022] Open
Abstract
Glioma is one of the most commonly diagnosed intracranial malignancies. The molecular mechanism underlying the development of glioma is still largely unknown. In this study, we present the first report concerning the function and mechanism of cyclin‐dependent kinase‐like 3 (CDKL3) in the development and prognosis of glioma. It is shown that CDKL3 was upregulated in glioma tissues and could independently predict poor prognosis of patients. Silencing CDKL3 in glioma cells could inhibit cell proliferation and migration and induce cell apoptosis and cell cycle arrest, whereas the overexpression of CDKL3 promoted cell proliferation. The in vivo experiments also indicated that knockdown of CDKL3 significantly suppressed tumor growth of glioma. Gene expression profiling of CDKL3 knockdown U87 cells identified RRM2 as a potential target of CDKL3, which was proved to have direct interaction with CDKL3. Given similar effects on glioma development with CDKL3, knockdown of RRM2 could rescue the effects of CDKL3 overexpression on glioma cells. Moreover, knockdown of CDKL3 or RRM2 suppressed the activity of JNK signaling, whereas CDKL3 overexpression produced the opposite effect. In conclusion, our results identified CDKL3 as a promotor for glioma, probably through the regulation of RRM2 and activation of the JNK signalling pathway, highlighting the significance of CDKL3 as a promising therapeutic target of glioma.
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Affiliation(s)
- Yong Cui
- Department of Neurosurgery, Third Affiliated Hospital, Naval Medical University, Shanghai, China
| | - Zhigang Yang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hongxiang Wang
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Yong Yan
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Qilin Huang
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhenyu Gong
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Fan Hong
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xu Zhang
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Weiqing Li
- Department of Pathology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Juxiang Chen
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Tao Xu
- Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China
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Ranjan A, Pang Y, Butler M, Merchant M, Kim O, Yu G, Su YT, Gilbert MR, Levens D, Wu J. Targeting CDK9 for the Treatment of Glioblastoma. Cancers (Basel) 2021; 13:3039. [PMID: 34207158 PMCID: PMC8234280 DOI: 10.3390/cancers13123039] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma is the most common and aggressive primary malignant brain tumor, and more than two-thirds of patients with glioblastoma die within two years of diagnosis. The challenges of treating this disease mainly include genetic and microenvironmental features that often render the tumor resistant to treatments. Despite extensive research efforts, only a small number of drugs tested in clinical trials have become therapies for patients. Targeting cyclin-dependent kinase 9 (CDK9) is an emerging therapeutic approach that has the potential to overcome the challenges in glioblastoma management. Here, we discuss how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response to facilitate an anti-tumor response. Moreover, we discuss small-molecule inhibitors of CDK9 in clinical trials and future perspectives on the use of CDK9 inhibitors in treating patients with glioblastoma.
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Affiliation(s)
- Alice Ranjan
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - Ying Pang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - Madison Butler
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - Mythili Merchant
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - Olga Kim
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - Guangyang Yu
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - Yu-Ting Su
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - Mark R. Gilbert
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
| | - David Levens
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA;
| | - Jing Wu
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; (A.R.); (Y.P.); (M.B.); (M.M.); (O.K.); (G.Y.); (Y.-T.S.); (M.R.G.)
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Kałuzińska Ż, Kołat D, Bednarek AK, Płuciennik E. PLEK2, RRM2, GCSH: A Novel WWOX-Dependent Biomarker Triad of Glioblastoma at the Crossroads of Cytoskeleton Reorganization and Metabolism Alterations. Cancers (Basel) 2021; 13:2955. [PMID: 34204789 PMCID: PMC8231639 DOI: 10.3390/cancers13122955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/30/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma is one of the deadliest human cancers. Its malignancy depends on cytoskeleton reorganization, which is related to, e.g., epithelial-to-mesenchymal transition and metastasis. The malignant phenotype of glioblastoma is also affected by the WWOX gene, which is lost in nearly a quarter of gliomas. Although the role of WWOX in the cytoskeleton rearrangement has been found in neural progenitor cells, its function as a modulator of cytoskeleton in gliomas was not investigated. Therefore, this study aimed to investigate the role of WWOX and its collaborators in cytoskeleton dynamics of glioblastoma. Methodology on RNA-seq data integrated the use of databases, bioinformatics tools, web-based platforms, and machine learning algorithm, and the obtained results were validated through microarray data. PLEK2, RRM2, and GCSH were the most relevant WWOX-dependent genes that could serve as novel biomarkers. Other genes important in the context of cytoskeleton (BMP4, CCL11, CUX2, DUSP7, FAM92B, GRIN2B, HOXA1, HOXA10, KIF20A, NF2, SPOCK1, TTR, UHRF1, and WT1), metabolism (MTHFD2), or correlation with WWOX (COL3A1, KIF20A, RNF141, and RXRG) were also discovered. For the first time, we propose that changes in WWOX expression dictate a myriad of alterations that affect both glioblastoma cytoskeleton and metabolism, rendering new therapeutic possibilities.
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Affiliation(s)
- Żaneta Kałuzińska
- Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland; (D.K.); (A.K.B.); (E.P.)
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Zhang S, Peng X, Li X, Liu H, Zhao B, Elkabets M, Liu Y, Wang W, Wang R, Zhong Y, Kong D. BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair. Cell Death Dis 2021; 12:546. [PMID: 34039959 PMCID: PMC8150626 DOI: 10.1038/s41419-021-03805-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/06/2021] [Accepted: 05/06/2021] [Indexed: 02/05/2023]
Abstract
PARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of "synthetic lethality". However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker γ-H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.
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Affiliation(s)
- Shaolu Zhang
- grid.265021.20000 0000 9792 1228Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China ,grid.410740.60000 0004 1803 4911State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Xin Peng
- grid.265021.20000 0000 9792 1228Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Xiaofei Li
- grid.265021.20000 0000 9792 1228Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Hongyan Liu
- grid.410740.60000 0004 1803 4911State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Baoquan Zhao
- grid.410740.60000 0004 1803 4911State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Moshe Elkabets
- grid.7489.20000 0004 1937 0511The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Yao Liu
- grid.417024.40000 0004 0605 6814Department of Otorhinolaryngology Head and Neck, Institute of Otorhinolaryngology, Tianjin First Central Hospital, Tianjin, China
| | - Wei Wang
- grid.417024.40000 0004 0605 6814Department of Otorhinolaryngology Head and Neck, Institute of Otorhinolaryngology, Tianjin First Central Hospital, Tianjin, China
| | - Ran Wang
- grid.265021.20000 0000 9792 1228Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Yuxu Zhong
- grid.410740.60000 0004 1803 4911State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China
| | - Dexin Kong
- grid.265021.20000 0000 9792 1228Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China ,School of Medicine, Tianjin Tianshi College, Tianyuan University, Tianjin, China
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45
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BRCA1 degradation in response to mitochondrial damage in breast cancer cells. Sci Rep 2021; 11:8735. [PMID: 33888730 PMCID: PMC8062582 DOI: 10.1038/s41598-021-87698-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
BRCA1 is a well-studied tumor suppressor involved in the homologous repair of DNA damage, whereas PINK1, a mitochondrial serine/threonine kinase, is known to be involved in mitochondrial quality control. Genetic mutations of PINK1 and Parkin cause autosomal recessive early-onset Parkinson's disease. We found that in breast cancer cells, the mitochondrial targeting reagents, which all induce mitochondrial depolarization along with PINK1 upregulation, induced proteasomal BRCA1 degradation. This BRCA1 degradation was dependent on PINK1, and BRCA1 downregulation upon mitochondrial damage caused DNA double-strand breaks. BRCA1 degradation was mediated through the direct interaction with the E3 ligase Parkin. Strikingly, BRCA1 and PINK1/Parkin expression were inversely correlated in cancerous mammary glands from breast cancer patients. BRCA1 knockdown repressed cancer cell growth, and high BRCA1 expression predicted poor relapse-free survival in breast cancer patients. These observations indicate a novel mechanism by which mitochondrial damage is transmitted to the nucleus, leading to BRCA1 degradation.
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46
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Holst CB, Pedersen H, Obara EAA, Vitting-Seerup K, Jensen KE, Skjøth-Rasmussen J, Lund EL, Poulsen HS, Johansen JS, Hamerlik P. Perspective: targeting VEGF-A and YKL-40 in glioblastoma - matter matters. Cell Cycle 2021; 20:702-715. [PMID: 33779510 PMCID: PMC8078714 DOI: 10.1080/15384101.2021.1901037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Glioblastomas (GBM) are heterogeneous highly vascular brain tumors exploiting the unique microenvironment in the brain to resist treatment and anti-tumor responses. Anti-angiogenic agents, immunotherapy, and targeted therapy have been studied extensively in GBM patients over a number of decades with minimal success. Despite maximal efforts, prognosis remains dismal with an overall survival of approximately 15 months. Bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) antibody, underwent accelerated approval by the U.S. Food and Drug Administration in 2009 for the treatment of recurrent GBM based on promising preclinical and early clinical studies. Unfortunately, subsequent clinical trials did not find overall survival benefit. Pursuing pleiotropic targets and leaning toward multitarget strategies may be a key to more effective therapeutic intervention in GBM, but preclinical evaluation requires careful consideration of model choices. In this study, we discuss bevacizumab resistance, dual targeting of pro-angiogenic modulators VEGF and YKL-40 in the context of brain tumor microenvironment, and how model choice impacts study conclusions and its translational significance.
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Affiliation(s)
- Camilla Bjørnbak Holst
- Department of Medicine, Herlev and Gentofte Hospital, Herlev, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark.,Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.,Department of Radiation Biology, Department of Oncology, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Henriette Pedersen
- Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
| | | | - Kristoffer Vitting-Seerup
- Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
| | - Kamilla Ellermann Jensen
- Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
| | | | - Eva Løbner Lund
- Department of Pathology, Rigshospitalet, Copenhagen, Denmark
| | - Hans Skovgaard Poulsen
- Department of Radiation Biology, Department of Oncology, Rigshospitalet, Copenhagen, Denmark
| | - Julia Sidenius Johansen
- Department of Medicine, Herlev and Gentofte Hospital, Herlev, Denmark.,Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Petra Hamerlik
- Brain Tumor Biology, Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
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47
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Tuy K, Rickenbacker L, Hjelmeland AB. Reactive oxygen species produced by altered tumor metabolism impacts cancer stem cell maintenance. Redox Biol 2021; 44:101953. [PMID: 34052208 PMCID: PMC8212140 DOI: 10.1016/j.redox.2021.101953] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/11/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023] Open
Abstract
Controlling reactive oxygen species (ROS) at sustainable levels can drive multiple facets of tumor biology, including within the cancer stem cell (CSC) population. Tight regulation of ROS is one key component in CSCs that drives disease recurrence, cell signaling, and therapeutic resistance. While ROS are well-appreciated to need oxygen and are a product of oxidative phosphorylation, there are also important roles for ROS under hypoxia. As hypoxia promotes and sustains major stemness pathways, further consideration of ROS impacts on CSCs in the tumor microenvironment is important. Furthermore, glycolytic shifts that occur in cancer and may be promoted by hypoxia are associated with multiple mechanisms to mitigate oxidative stress. This altered metabolism provides survival advantages that sustain malignant features, such as proliferation and self-renewal, while producing the necessary antioxidants that reduce damage from oxidative stress. Finally, disease recurrence is believed to be attributed to therapy resistant CSCs which can be quiescent and have changes in redox status. Effective DNA damage response pathways and/or a slow-cycling state can protect CSCs from the genomic catastrophe induced by irradiation and genotoxic agents. This review will explore the delicate, yet complex, relationship between ROS and its pleiotropic role in modulating the CSC.
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Affiliation(s)
- Kaysaw Tuy
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lucas Rickenbacker
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
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48
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Baroni M, Yi C, Choudhary S, Lei X, Kosti A, Grieshober D, Velasco M, Qiao M, Burns SS, Araujo PR, DeLambre T, Son MY, Plateroti M, Ferreira MAR, Hasty EP, Penalva LOF. Musashi1 Contribution to Glioblastoma Development via Regulation of a Network of DNA Replication, Cell Cycle and Division Genes. Cancers (Basel) 2021; 13:1494. [PMID: 33804958 PMCID: PMC8036803 DOI: 10.3390/cancers13071494] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/17/2021] [Accepted: 03/21/2021] [Indexed: 11/21/2022] Open
Abstract
RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in their levels are often observed in tumors with numerous oncogenic RBPs identified in recent years. Musashi1 (Msi1) is an RBP and stem cell gene that controls the balance between self-renewal and differentiation. High Msi1 levels have been observed in multiple tumors including glioblastoma and are often associated with poor patient outcomes and tumor growth. A comprehensive genomic analysis identified a network of cell cycle/division and DNA replication genes and established these processes as Msi1's core regulatory functions in glioblastoma. Msi1 controls this gene network via two mechanisms: direct interaction and indirect regulation mediated by the transcription factors E2F2 and E2F8. Moreover, glioblastoma lines with Msi1 knockout (KO) displayed increased sensitivity to cell cycle and DNA replication inhibitors. Our results suggest that a drug combination strategy (Msi1 + cell cycle/DNA replication inhibitors) could be a viable route to treat glioblastoma.
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Affiliation(s)
- Mirella Baroni
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Caihong Yi
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
- Third Xiangya Hospital, Central South University, Changsha 410000, China
| | - Saket Choudhary
- Computational Biology and Bioinformatics, University of Southern California, Los Angeles, CA 90089, USA;
| | - Xiufen Lei
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Adam Kosti
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA
| | - Denise Grieshober
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Mitzli Velasco
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Mei Qiao
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Suzanne S. Burns
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Patricia R. Araujo
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Talia DeLambre
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
| | - Mi Young Son
- Department of Molecular Medicine, Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX 78229, USA; (M.Y.S.); (E.P.H.)
| | - Michelina Plateroti
- Team: Development, Cancer and Stem Cells, Université de Strasbourg, Inserm, IRFAC/UMR-S1113, FMTS, 67200 Strasbourg, France;
| | | | - E. Paul Hasty
- Department of Molecular Medicine, Sam and Ann Barshop Institute for Longevity and Aging Studies, UT Health San Antonio, San Antonio, TX 78229, USA; (M.Y.S.); (E.P.H.)
| | - Luiz O. F. Penalva
- Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX 78229, USA; (M.B.); (C.Y.); (X.L.); (A.K.); (D.G.); (M.V.); (M.Q.); (P.R.A.); (T.D.)
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX 78229, USA
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49
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Rieunier G, Wu X, Harris LE, Mills JV, Nandakumar A, Colling L, Seraia E, Hatch SB, Ebner DV, Folkes LK, Weyer-Czernilofsky U, Bogenrieder T, Ryan AJ, Macaulay VM. Targeting IGF Perturbs Global Replication through Ribonucleotide Reductase Dysfunction. Cancer Res 2021; 81:2128-2141. [PMID: 33509941 DOI: 10.1158/0008-5472.can-20-2860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 12/17/2020] [Accepted: 01/22/2021] [Indexed: 11/16/2022]
Abstract
Inhibition of IGF receptor (IGF1R) delays repair of radiation-induced DNA double-strand breaks (DSB), prompting us to investigate whether IGF1R influences endogenous DNA damage. Here we demonstrate that IGF1R inhibition generates endogenous DNA lesions protected by 53BP1 bodies, indicating under-replicated DNA. In cancer cells, inhibition or depletion of IGF1R delayed replication fork progression accompanied by activation of ATR-CHK1 signaling and the intra-S-phase checkpoint. This phenotype reflected unanticipated regulation of global replication by IGF1 mediated via AKT, MEK/ERK, and JUN to influence expression of ribonucleotide reductase (RNR) subunit RRM2. Consequently, inhibition or depletion of IGF1R downregulated RRM2, compromising RNR function and perturbing dNTP supply. The resulting delay in fork progression and hallmarks of replication stress were rescued by RRM2 overexpression, confirming RRM2 as the critical factor through which IGF1 regulates replication. Suspecting existence of a backup pathway protecting from toxic sequelae of replication stress, targeted compound screens in breast cancer cells identified synergy between IGF inhibition and ATM loss. Reciprocal screens of ATM-proficient/deficient fibroblasts identified an IGF1R inhibitor as the top hit. IGF inhibition selectively compromised growth of ATM-null cells and spheroids and caused regression of ATM-null xenografts. This synthetic-lethal effect reflected conversion of single-stranded lesions in IGF-inhibited cells into toxic DSBs upon ATM inhibition. Overall, these data implicate IGF1R in alleviating replication stress, and the reciprocal IGF:ATM codependence we identify provides an approach to exploit this effect in ATM-deficient cancers. SIGNIFICANCE: This study identifies regulation of ribonucleotide reductase function and dNTP supply by IGFs and demonstrates that IGF axis blockade induces replication stress and reciprocal codependence on ATM. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2128/F1.large.jpg.
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Affiliation(s)
| | - Xiaoning Wu
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Letitia E Harris
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Jack V Mills
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Ashwin Nandakumar
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Laura Colling
- Department of Oncology, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom
| | - Elena Seraia
- Target Discovery Institute, University of Oxford, Oxford, United Kingdom
| | - Stephanie B Hatch
- Target Discovery Institute, University of Oxford, Oxford, United Kingdom
| | - Daniel V Ebner
- Target Discovery Institute, University of Oxford, Oxford, United Kingdom
| | - Lisa K Folkes
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | | | - Thomas Bogenrieder
- AMAL Therapeutics, Geneva, Switzerland
- Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany
| | - Anderson J Ryan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom
| | - Valentine M Macaulay
- Department of Oncology, University of Oxford, Oxford, United Kingdom.
- Oxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, United Kingdom
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50
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Haugaard-Kedström LM, Clemmensen LS, Sereikaite V, Jin Z, Fernandes EFA, Wind B, Abalde-Gil F, Daberger J, Vistrup-Parry M, Aguilar-Morante D, Leblanc R, Egea-Jimenez AL, Albrigtsen M, Jensen KE, Jensen TMT, Ivarsson Y, Vincentelli R, Hamerlik P, Andersen JH, Zimmermann P, Lee W, Strømgaard K. A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma. J Med Chem 2021; 64:1423-1434. [PMID: 33502198 DOI: 10.1021/acs.jmedchem.0c00382] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Despite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, comprising two postsynaptic density protein-95/discs-large/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL-128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.
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Affiliation(s)
- Linda M Haugaard-Kedström
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Louise S Clemmensen
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Vita Sereikaite
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Zeyu Jin
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 120-749 Seoul, Korea
| | - Eduardo F A Fernandes
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Bianca Wind
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Flor Abalde-Gil
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Jan Daberger
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Maria Vistrup-Parry
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Diana Aguilar-Morante
- Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark
| | - Raphael Leblanc
- Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France
| | - Antonio L Egea-Jimenez
- Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.,Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium
| | - Marte Albrigtsen
- Marbio, UiT-The Artic University of Norway, N-9037 Tromsø, Norway
| | - Kamilla E Jensen
- Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark
| | - Thomas M T Jensen
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
| | - Ylva Ivarsson
- Department of Chemistry-BMC, Uppsala University, SE-751 23 Uppsala, Sweden
| | - Renaud Vincentelli
- Unité Mixte de Recherche (UMR) 7257, Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Université, Architecture et Fonction des Macromolécules Biologiques (AFMB), Campus de Luminy, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France
| | - Petra Hamerlik
- Brain Tumor Biology Group, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark
| | | | - Pascale Zimmermann
- Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, 13009 Marseille, France.,Department of Human Genetics, KU Leuven, ON1 Herestraat 49 Box 602, B-3000 Leuven, Belgium
| | - Weontae Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 120-749 Seoul, Korea
| | - Kristian Strømgaard
- Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
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