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Jeyaraman K, Concolino P, Falhammar H. Adrenocortical tumors and hereditary syndromes. Expert Rev Endocrinol Metab 2025; 20:1-19. [PMID: 39570085 DOI: 10.1080/17446651.2024.2431748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 11/15/2024] [Indexed: 11/22/2024]
Abstract
INTRODUCTION Adrenocortical tumors (ACTs) are frequently encountered in clinical practice. They vary in clinical and biological characteristics from nonfunctional to life threatening hormone excess, from benign to highly aggressive malignant tumors. Most ACTs appear to be benign and nonfunctioning. It has been controversial how these apparently benign and nonfunctioning tumors should be monitored. Over the past few decades, significant advances have been made in understanding the regulation of growth and tumorigenesis in adrenocortical cells. Defining the molecular pathomechanisms in inherited tumor syndromes led to the expansion of research to sporadic ACTs. Distinct molecular signatures have been identified in sporadic ACTs and a potential genomic classification of ACT has been proposed. AREAS COVERED In this review, we discuss the various adrenocortical pathologies associated with hereditary syndromes with special focus on their molecular pathomechanisms, the understanding of which is important in the era of precision medicine. EXPERT OPINION Identifying the molecular pathomechanisms of the adrenocortical tumorigenesis in inherited syndromes has led to the understanding of the alterations in different signaling pathways that help explain the wide variations in the biology and behavior of ACTs.
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Affiliation(s)
| | - Paola Concolino
- Dipartimento di Scienze di Laboratorio ed Ematologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
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Godizzi F, Armando F, Boracchi P, Avallone G, Stefanello D, Ferrari R, Chiti LE, Cappelleri A, Zamboni C, Dell'Aere S, Corradi A, Roccabianca P. Survivin, β-catenin, and ki-67 immunohistochemical expression in canine perivascular wall tumors: Preliminary assessment of prognostic significance. Vet Pathol 2024; 61:912-927. [PMID: 38727195 DOI: 10.1177/03009858241246981] [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] [Indexed: 11/05/2024]
Abstract
High survivin expression has been correlated with poor outcomes in several canine tumors but not in soft tissue tumors (STTs). Survivin is a target gene of the Wnt/β-catenin pathway, which is involved in human STT oncogenesis. Immunohistochemistry for survivin, β-catenin, and Ki-67 was performed on 41 canine perivascular wall tumors (cPWTs), and statistical associations of protein expression and histopathologic and clinical variables with clinical outcomes were investigated. Immunohistochemically, there was nuclear positivity (0.9%-12.2% of tumor cells) for survivin in 41/41 (100%), cytoplasmic positivity (0 to > 75% of tumor cells) for survivin in 31/41 (76%), nuclear positivity (2.9%-67.2% of tumor cells) for β-catenin in 24/41 (59%), and cytoplasmic positivity (0% to > 75% of tumor cells) for β-catenin in 23/41 (56%) of cPWTs. All tumors expressed nuclear Ki-67 (2.2%-23.5%). In univariate analysis and multivariate analysis (UA and MA, respectively), every 1% increase of nuclear survivin was associated with an increase of the instantaneous death risk by a factor of 1.15 [hazard ratio (HR) = 1.15; P = .007]. Higher nuclear survivin was associated with grade II/III neoplasms (P = .043). Expression of cytoplasmic survivin, nuclear and cytoplasmic β-catenin, and nuclear Ki-67 were not significantly associated with prognosis in UA nor MA. Tumor size was a significant prognostic factor for local recurrence in UA [subdistribution HR (SDHR) = 1.19; P = .02] and for reduced overall survival time in MA. According to UA and MA, a unitary increase of mitotic count was associated with an increase of the instantaneous death risk by a factor of 1.05 (HR = 1.05; P = .014). Nuclear survivin, mitotic count, and tumor size seem to be potential prognostic factors for cPWTs. In addition, survivin and β-catenin may represent promising therapeutic targets for cPWTs.
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Affiliation(s)
- Francesco Godizzi
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Federico Armando
- Department of Pathology, University of Veterinary Medicine, Foundation, Hannover, Germany
| | - Patrizia Boracchi
- Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy
| | - Giancarlo Avallone
- Department of Veterinary Medical Sciences (DIMEVET), University of Bologna, Ozzano dell'Emilia, Italy
| | - Damiano Stefanello
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Roberta Ferrari
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Lavinia E Chiti
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Andrea Cappelleri
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
- Mouse and Animal Pathology Laboratory (MAPLab), Fondazione UniMi, Milan, Italy
| | - Clarissa Zamboni
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Silvia Dell'Aere
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
| | - Attilio Corradi
- Department of Veterinary Science, University of Parma, Parma, Italy
| | - Paola Roccabianca
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi, Italy
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Tian X, Zhang C, Wang D, Li X, Wang Q. Ginseng polysaccharide promotes the apoptosis of colon cancer cells via activating the NLRP3 inflammasome. Immunopharmacol Immunotoxicol 2024:1-12. [PMID: 39219032 DOI: 10.1080/08923973.2024.2398472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Ginseng polysaccharide (GPS) is an ingredient of ginseng with documented anti-tumor properties. However, its effect on colon cancer and the underlying molecular mechanisms have not been investigated clearly. METHODS Cell viability of HT29 and CT26 cells treated with different concentrations of GPS was assessed using the Cell Counting Kit-8 (CCK-8) assay. Western blot assay was used to detect the expression of apoptotic proteins, while the mRNA levels were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). Transwell migration assays were used to examine the migration and invasion of cells. RESULTS The results revealed that GPS effectively suppressed the proliferation of HT29 and CT26 cells. We demonstrated an upregulation of apoptotic proteins in GPS-treated cells, including Bax, cleaved Caspase-3, and p-p53. GPS treatment also increased the mRNA levels of cytochrome C and Bax. Furthermore, the results showed that GPS treatment concurrently promoted the activation of nucleotide-binding domain leucine-rich family pyrin-containing 3 (NLRP3) inflammasome. Transwell migration assays showed that GPS inhibited the migratory and invasive abilities of colon cancer cells. As expected, inhibition of NLRP3 expression using INF39 attenuated the inhibitory effect of GPS on migration and invasion. Upon NLRP3 inhibition, GPS-induced apoptosis was dramatically alleviated, accompanied by a reduction in the expression of apoptotic proteins. CONCLUSION In conclusion, this research provides compelling evidence that the GPS-induced NLRP3 signaling pathway plays a pivotal role in apoptosis of colon cells, suggesting potential clinical implications for the therapeutic intervention of colon cancer. Thus, GPS might be a promising anti-tumor drug for the treatment of colorectal cancer.
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Affiliation(s)
- Xiaoyan Tian
- Department of General Surgery, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Chuanqiang Zhang
- Department of General Surgery, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Daojuan Wang
- Department of Pain, The Affiliated Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaowei Li
- Department of General Surgery, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
| | - Qiang Wang
- Department of General Surgery, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, Jiangsu, China
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Gao B, Qiao Y, Zhu S, Yang N, Zou SS, Liu YJ, Chen J. USP36 inhibits apoptosis by deubiquitinating cIAP1 and survivin in colorectal cancer cells. J Biol Chem 2024; 300:107463. [PMID: 38876304 PMCID: PMC11268115 DOI: 10.1016/j.jbc.2024.107463] [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: 03/04/2024] [Revised: 05/19/2024] [Accepted: 05/30/2024] [Indexed: 06/16/2024] Open
Abstract
Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11-linked ubiquitin chains from cIAP1 and lysine-48-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.
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Affiliation(s)
- Bao Gao
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China; Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yuan Qiao
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Shan Zhu
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China; Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ning Yang
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Shan-Shan Zou
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yong-Jun Liu
- Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, Jilin, China.
| | - Jingtao Chen
- Cancer Center, First Hospital of Jilin University, Changchun, Jilin, China; Laboratory for Tumor Immunology, First Hospital of Jilin University, Changchun, Jilin, China.
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Li Q, Liu H, Wang H, Xiong W, Dai L, Zhang X, Wang P, Ye H, Shi J, Fang Z, Wang K. Anti-BIRC5 autoantibody serves as a valuable biomarker for diagnosing AFP-negative hepatocellular carcinoma. PeerJ 2024; 12:e17494. [PMID: 38832035 PMCID: PMC11146321 DOI: 10.7717/peerj.17494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 05/09/2024] [Indexed: 06/05/2024] Open
Abstract
Background Autoantibodies targeting tumor-associated antigens (TAAbs) have emerged as promising biomarkers for early cancer detection. This research aimed to assess the diagnostic capacity of anti-BIRC5 autoantibody in detecting AFP-negative hepatocellular carcinoma (ANHCC). Methods This research was carried out in three stages (discovery phase, validation phase, and evaluation phase) and included a total of 744 participants. Firstly, the anti-BIRC5 autoantibody was discovered using protein microarray, exhibiting a higher positive rate in ANHCC samples (ANHCCs) compared to normal control samples (NCs). Secondly, the anti-BIRC5 autoantibody was validated through enzyme-linked immunosorbent assay (ELISA) in 85 ANHCCs and 85 NCs from two clinical centers (Zhengzhou and Nanchang). Lastly, the diagnostic usefulness of the anti-BIRC5 autoantibody for hepatocellular carcinoma (HCC) was evaluated by ELISA in a cohort consisting of an additional 149 AFP-positive hepatocellular carcinoma samples (APHCCs), 95 ANHCCs and 244 NCs. The association of elevated autoantibody to high expression of BIRC5 in HCC was further explored by the database from prognosis, immune infiltration, DNA methylation, and gene mutation level. Results In the validation phase, the area under the ROC curve (AUC) of anti-BIRC5 autoantibody to distinguish ANHCCs from NCs in Zhengzhou and Nanchang centers was 0.733 and 0.745, respectively. In the evaluation phase, the AUCs of anti-BIRC5 autoantibody for identifying ANHCCs and HCCs from NCs were 0.738 and 0.726, respectively. Furthermore, when combined with AFP, the AUC for identifying HCCs from NCs increased to 0.914 with a sensitivity of 77.5% and specificity of 91.8%. High expression of BIRC5 gene is not only correlated with poor prognosis of HCCs, but also significantly associated with infiltration of immune cells, DNA methylation, and gene mutation. Conclusion The findings suggest that the anti-BIRC5 autoantibody could serve as a potential biomarker for ANHCC, in addition to its supplementary role alongside AFP in the diagnosis of HCC. Next, we can carry out specific verification and explore the function of anti-BIRC5 autoantibody in the occurrence and development of HCC.
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Affiliation(s)
- Qing Li
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Haiyan Liu
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Han Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Wenzhuo Xiong
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Liping Dai
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Xiuzhi Zhang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
- Department of Pathology, Henan Medical College, Zhengzhou, Henan, China
| | - Peng Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Hua Ye
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jianxiang Shi
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
| | - Zhihao Fang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Keyan Wang
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
- School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Henan Key Medical Laboratory of Tumor Molecular Biomarkers, Zhengzhou, China
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Wang Q, Greene MI. Survivin as a Therapeutic Target for the Treatment of Human Cancer. Cancers (Basel) 2024; 16:1705. [PMID: 38730657 PMCID: PMC11083197 DOI: 10.3390/cancers16091705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/17/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.
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Affiliation(s)
- Qiang Wang
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mark I. Greene
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Kitagawa T, Matsumoto T, Ohta T, Yoshida T, Saito Y, Nakayama Y, Hadate Y, Ashihara E, Watanabe T. Linderapyrone analogue LPD-01 as a cancer treatment agent by targeting importin7. J Nat Med 2024; 78:370-381. [PMID: 38265612 DOI: 10.1007/s11418-023-01774-y] [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: 11/11/2023] [Accepted: 12/12/2023] [Indexed: 01/25/2024]
Abstract
The Wnt/β-catenin signaling pathway plays important roles in several cancer cells, including cell proliferation and development. We previously succeeded in synthesizing a small molecule compound inhibiting the Wnt/β-catenin signaling pathway, named LPD-01 (1), and 1 inhibited the growth of human colorectal cancer (HT-29) cells. In this study, we revealed that 1 inhibits the growth of HT-29 cells stronger than that of another human colorectal cancer (SW480) cells. Therefore, we have attempted to identify the target proteins of 1 in HT-29 cells. Firstly, we investigated the effect on the expression levels of the Wnt/β-catenin signaling pathway-related proteins. As a result, 1 inhibited the expression of target proteins of Wnt/β-catenin signaling pathway (c-Myc and Survivin) and their genes, whereas the amount of transcriptional co-activator (β-catenin) was not decreased, suggesting that 1 inhibited the Wnt/β-catenin signaling pathway without affecting β-catenin. Next, we investigated the target proteins of 1 using magnetic FG beads. Chemical pull-down assay combined with mass spectrometry suggested that 1 directly binds to importin7. As expected, 1 inhibited the nuclear translocation of importin7 cargoes such as Smad2 and Smad3 in TGF-β-stimulated HT-29 cells. In addition, the knockdown of importin7 by siRNA reduced the expression of target genes of Wnt/β-catenin signaling pathway. These results suggest that importin7 is one of the target proteins of 1 for inhibition of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Takahiro Kitagawa
- Laboratory of Public Health, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607-8412, Japan
| | - Takahiro Matsumoto
- Laboratory of Public Health, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607-8412, Japan.
| | - Tomoe Ohta
- Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki, 859-3298, Japan
| | - Tatsusada Yoshida
- Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki, 859-3298, Japan
| | - Youhei Saito
- Laboratory of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607-8412, Japan
| | - Yuji Nakayama
- Laboratory of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607-8412, Japan
| | - Yuki Hadate
- Laboratory of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607-8412, Japan
| | - Eishi Ashihara
- Laboratory of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607-8412, Japan
| | - Tetsushi Watanabe
- Laboratory of Public Health, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto, 607-8412, Japan.
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Guo M, Li X, Li J, Li B. Identification of the prognostic biomarkers and their correlations with immune infiltration in colorectal cancer through bioinformatics analysis and in vitro experiments. Heliyon 2023; 9:e17101. [PMID: 37389063 PMCID: PMC10300223 DOI: 10.1016/j.heliyon.2023.e17101] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/01/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer death. The objective was to identify novel hub genes that were helpful for prognosis and targeted therapy in CRC. GSE23878, GSE24514, GSE41657, GSE81582 were filtered from the gene expression omnibus (GEO). Differentially expressed genes (DEGs) were identified through GEO2R, which were enriched in the GO term and KEGG pathway in DAVID. PPI network was constructed and analyzed using STRING and hub genes were screened out. The relationships between hub genes and prognoses in CRC were evaluated in GEPIA based on the cancer genome atlas (TCGA) and genotype-tissue expression (GTEx). The transcription factors and miRNA-mRNA interaction networks for hub genes were performed using miRnet and miRTarBase. The relationship between hub genes and tumor-infiltrating lymphocytes were analyzed in TIMER. The protein levels of hub genes were identified in HPA. The expression levels of hub gene in CRC and its effect on the biological effect of CRC cells were identified in vitro. As hub genes, the mRNA levels of BIRC5, CCNB1, KIF20A, NCAPG, and TPX2 were highly expressed in CRC and had excellent prognostic value. The BIRC5, CCNB1, KIF20A, NCAPG, and TPX2 were closely associated with transcription factors, miRNAs, tumor-infiltrating lymphocytes, suggesting their involvement in the regulation of CRC. BIRC5 highly expressed in CRC tissues and cells, and promoted the proliferation, migration, and invasion of CRC cells. BIRC5, CCNB1, KIF20A, NCAPG, and TPX2 are hub genes that serve as promising prognostic biomarkers in CRC. BIRC5 plays an important role in the development and progression of CRC.
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Affiliation(s)
- Min Guo
- Department of Oncology, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaxi Li
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Jiong Li
- Department of Anatomy, Neuroscience Laboratory for Cognitive and Developmental Disorders, Medical College of Jinan University, Guangzhou, Guangdong, China
| | - Baolong Li
- Department of General Surgery, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Bär SI, Pradhan R, Biersack B, Nitzsche B, Höpfner M, Schobert R. New chimeric HDAC inhibitors for the treatment of colorectal cancer. Arch Pharm (Weinheim) 2023; 356:e2200422. [PMID: 36442846 DOI: 10.1002/ardp.202200422] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/30/2022]
Abstract
Colorectal cancer is the third most common cause of cancer-associated deaths due to a high recurrence rate and an increasing occurrence of resistance to established therapies. This highlights the importance of developing new chemotherapeutic agents. The current study focuses on cancer-specific targets such as apoptosis-inhibiting survivin, which distinguishes cancer cells from healthy tissue. A combination of pharmacophores of established anticancer agents to afford chimeric pleiotropic chemotherapeutic agents was tested on this cancer entity. We analysed the effects of the dual mode anticancer agents, animthioxam, brimbam, troxbam, and troxham, as well as their structural congeners suberoylanilide hydroxamic acid and combretastatin A-4 on human cancer cell lines. Their cytotoxicity was determined using the MTT assay, further techniques for detecting apoptotic events, cell cycle analyses, clonogenic and wound healing assays, immunostaining, histone deacetylase (HDAC) activity measurements, and Western blot analysis for the detection of survivin expression in HCT116 colon cancer cells. Molecular docking studies were conducted to assess potential molecular targets of the test compounds. The test compounds were found selectively cytotoxic toward cancer cells by inducing apoptosis. The metastatic potential was effectively reduced by disruption of the microtubular cytoskeleton. The test compounds were also proven to be general HDAC inhibitors and to lead to reduced survivin expression.
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Affiliation(s)
- Sofia I Bär
- Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany
| | - Rohan Pradhan
- Care Group Sight Solution Pvt. Ltd., Dabhasa, Vadodara, India
| | - Bernhard Biersack
- Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany
| | - Bianca Nitzsche
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Michael Höpfner
- Institute of Physiology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Rainer Schobert
- Organic Chemistry Laboratory, University of Bayreuth, Bayreuth, Germany
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Parseh B, Khosravi A, Fazel A, Ai J, Ebrahimi-Barough S, Verdi J, Shahbazi M. 3-Dimensional Model to Study Apoptosis Induction of Activated Natural Killer Cells Conditioned Medium Using Patient-Derived Colorectal Cancer Organoids. Front Cell Dev Biol 2022; 10:895284. [PMID: 35721501 PMCID: PMC9204536 DOI: 10.3389/fcell.2022.895284] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 04/26/2022] [Indexed: 12/21/2022] Open
Abstract
Natural killer (NK) cells are innate lymphocytes that can kill tumor cells via different pathways, including the secretion of cytotoxic granules in immunological synapses and the binding of apoptosis-inducing ligands with cognate death receptors on tumor cells. These ligands are also soluble in NK cells conditioned medium (NK-CM). However, novel preclinical in vitro models are required for solid tumors such as colorectal cancer (CRC) to investigate apoptosis induction of activated NK-CM in a tissue-like structure. In the present study, we established a patient-derived CRC organoid culture system as a new tool for CRC research in the last decade. Tumor organoids were stained with hematoxylin and eosin (H&E) and compared with the original tumor taken from the patient. Goblet cell differentiation and mucus secretion were evaluated using periodic acid–Schiff and alcian blue histochemical staining. Moreover, tumor organoids were stained for CDX2 and Ki67 markers with immunohistochemistry (IHC) to investigate gastrointestinal origin and proliferation. Histopathological evaluations indicated tumor organoids represent patient tumor characteristics. Primary NK cells were isolated and characterized using CD56 marker expression and the lack of the CD3 marker. Flow cytometry results showed the purity of isolated CD3−and CD56 + NK cells about 93%. After further ex vivo expansion, IL-2-activated NK-CM was collected. Secretions of IFN-γ and TNF-α were measured to characterize activated NK-CM. Cytokines levels were significantly elevated in comparison to the control group. Soluble forms of apoptosis-inducing ligands, including TNF-related apoptosis-inducing ligand (TRAIL) and FasL, were detected by western blot assay. Colon cancer organoids were treated by IL-2-activated NK-CM. Apoptosis was assessed by Annexin V-FITC/PI staining and quantified by flow cytometry. In conclusion, despite the activated NK-CM containing apoptosis-inducing ligands, these ligands’ soluble forms failed to induce apoptosis in patient-derived colon cancer organoids. Nevertheless, we report a reliable in vitro assessment platform in a personalized setting.
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Affiliation(s)
- Benyamin Parseh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
| | - Ayyoob Khosravi
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
| | - Abdolreza Fazel
- Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Jafar Ai
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Verdi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Shahbazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
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11
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Swoboda J, Mittelsdorf P, Chen Y, Weiskirchen R, Stallhofer J, Schüle S, Gassler N. Intestinal Wnt in the transition from physiology to oncology. World J Clin Oncol 2022; 13:168-185. [PMID: 35433295 PMCID: PMC8966512 DOI: 10.5306/wjco.v13.i3.168] [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: 02/23/2021] [Revised: 09/07/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.
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Affiliation(s)
- Julia Swoboda
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Patrick Mittelsdorf
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Johannes Stallhofer
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena 07747, Germany
| | - Silke Schüle
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
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12
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Zhou P, Chen X, Shi K, Qu H, Xia J. The characteristics, tumorigenicities and therapeutics of cancer stem cells based on circRNAs. Pathol Res Pract 2022; 233:153822. [DOI: 10.1016/j.prp.2022.153822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/10/2022] [Accepted: 02/23/2022] [Indexed: 12/24/2022]
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13
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Reineking W, Schauerte IE, Junginger J, Hewicker-Trautwein M. Sox9, Hopx, and survivin and tuft cell marker DCLK1 expression in normal canine intestine and in intestinal adenoma and adenocarcinoma. Vet Pathol 2022; 59:415-426. [DOI: 10.1177/03009858221079666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Self-renewal of the intestinal epithelium originates from stem cells located at the crypt base. Upregulation of various stem cell markers in intestinal epithelial neoplasms indicates a potential role of stem cells in tumorigenesis. In this study, the immunoreactivity of potential intestinal stem cell markers ( Sry box transcription factor 9 [Sox9], homeodomain-only protein [Hopx], survivin) and tuft cell marker doublecortin-like kinase 1 (DCLK1) in normal canine intestine and intestinal epithelial neoplasms was investigated. Formalin-fixed paraffin-embedded (FFPE) small and large intestine as well as intestinal neoplasms (55 colorectal adenomas [CRAs], 17 small intestinal adenocarcinomas [SICs], and 12 colorectal adenocarcinomas [CRCs]) were analyzed immunohistologically. Potential stem cell markers Sox9, Hopx, and survivin were detected in the crypts of normal canine small and large intestine. DCLK1+ tuft cells were present in decreasing numbers along the crypt-villus axis of the jejunum and rarely detectable in large intestine. In canine intestinal epithelial tumors, nuclear Sox9 immunoreactivity was detectable in 84.9% (CRA), 80% (CRC), and 77% of epithelial neoplastic cells (SIC). Hopx and survivin were expressed within cytoplasm and nuclei of neoplastic cells in benign and malignant tumors. DCLK1 showed a cytoplasmic reaction within neoplastic cells. The combined score of Hopx, DCLK1, and survivin varied among the examined cases. Overall, malignant tumors showed lower DCLK1 scores but higher Hopx scores in comparison with benign tumors. For survivin, no differences were detectable. In conclusion, stem cell markers Sox9, Hopx, and survivin were detectable at the crypt base and the immunoreactivity of Sox9, DCLK1, survivin, and Hopx was increased in canine intestinal adenomas and adenocarcinomas compared with normal mucosa.
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14
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Zhang J, Xu X, Chen Y, Guan X, Zhu H, Qi Y. The abnormal expression of chromosomal region maintenance 1 (CRM1)-survivin axis in ovarian cancer and its related mechanisms regulating proliferation and apoptosis of ovarian cancer cells. Bioengineered 2022; 13:624-633. [PMID: 34898375 PMCID: PMC8805823 DOI: 10.1080/21655979.2021.2012416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/25/2021] [Indexed: 02/04/2023] Open
Abstract
Ovarian cancer (OC) is the main type of cancer that affects the female reproductive system and has a high morbidity and mortality rate. This study aimed to explore the regulatory effect of the chromosomal region maintenance 1 (CRM1)-survivin axis on the progression of OC. Ovarian cancer cells were transfected with pcDNA3.1-survivin and short hairpin RNA (sh)-CRM1. Cell proliferation was analyzed by cell counting kit-8 (CCK8), 5-ethynyl-2´-deoxyuridine (EdU) staining, and colony formation assays. Apoptosis was detected using flow cytometry. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze the expression of RNA and protein, respectively. qRT-PCR and prognostic correlation analyses revealed that CRM1 is highly expressed in OC cells and related to survival. The results of qRT-PCR, CCK8, colony formation test, EdU staining, flow cytometry, and Western blotting showed that CRM1 silencing inhibited the proliferation and colony formation of OVCAR 3 and SKOV3 cells and promoted cell apoptosis by promoting Caspase-3 activation. Survivin was positively regulated by CRM1 and promoted the development of OC. The results of the rescue experiment showed that overexpression of survivin reversed the inhibitory effect of CRM1 knockdown on the proliferation of ovarian cancer cells and its inhibitory effect on apoptosis. Our findings confirm the role of the CRM1-survivin signal transduction axis in OC by regulating the proliferation and apoptosis of OC cells, and may thus serve as a potential therapeutic target for OC.
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Affiliation(s)
- Jing Zhang
- Department of Gynecology, Urumqi Maternal and Child Health Hospital of Xinjiang Uygur, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Xinyan Xu
- Department of Gynecology, Urumqi Maternal and Child Health Hospital of Xinjiang Uygur, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Yongfeng Chen
- Pathology Department, Urumqi Maternal and Child Health Hospital of Xinjiang Uygur, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Xiaoju Guan
- Department of Gynecology, Urumqi Maternal and Child Health Hospital of Xinjiang Uygur, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Hong Zhu
- Department of Gynecology, Urumqi Maternal and Child Health Hospital of Xinjiang Uygur, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Yuhong Qi
- Department of Gynecology, Urumqi Maternal and Child Health Hospital of Xinjiang Uygur, Urumqi, Xinjiang Uygur Autonomous Region, China
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15
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Wang W, Yang C, Deng H. Overexpression of 15-Hydroxyprostaglandin Dehydrogenase Inhibits A549 Lung Adenocarcinoma Cell Growth via Inducing Cell Cycle Arrest and Inhibiting Epithelial-Mesenchymal Transition. Cancer Manag Res 2021; 13:8887-8900. [PMID: 34876851 PMCID: PMC8643138 DOI: 10.2147/cmar.s331222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/20/2021] [Indexed: 01/22/2023] Open
Abstract
Purpose Lung cancer is one of the most commonly diagnosed cancer as well as the leading cause of cancer-related mortality worldwide, among which lung adenocarcinoma (LUAD) is the most frequent form of lung cancer. Previous studies have shown that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of prostaglandins to reduce their biological activities and behaves as a tumor suppressor in various cancers. Thus, we aimed to systematically examine the effects of 15-PGDH overexpression on cellular processes in lung adenocarcinoma cells. Methods The stable 15-PGDH-overexpressing A549 cell line was constructed using lentivirus particles. CCK-8 assay was used to determine the cell proliferation rate and sensitivity to cisplatin. Tandem mass tag (TMT)-based quantitative proteomic analysis was used to identify differentially expressed proteins between control and 15-PGDH-overexpression cells. The cell cycle was determined by a flow cytometer. The expression levels of mesenchymal and epithelial markers were measured using Western blotting. Wound healing and transwell assays were used to detect the cell migration and cell invasion ability, respectively. Results Analysis of datasets in The Cancer Genome Atlas revealed that the PGDH gene expression level in the lung adenocarcinoma tissues was significantly lower than that in the pericarcinous tissues. 15-PGDH overexpression in A549 cells reduced cell proliferation rate. Quantitative proteomics revealed that 15-PGDH overexpression inhibited PI3K/AKT/mTOR signaling pathway, which is a signaling pathway driving tumor cell growth and epithelial-mesenchymal transition (EMT) process. In addition, both cell cycle and DNA repair-related proteins were down-regulated in 15-PGDH overexpressed cells. 15-PGDH overexpression induced G1/S cell cycle arrest and increased susceptibility to DNA damaging reagent cisplatin. Importantly, overexpression of 15-PGDH inhibited EMT process with the downregulation of β-catenin and Snail-1 as well as upregulation of E-cadherin and ZO-1. Conclusion 15-PGDH is a tumor suppressor in lung cancer and may serve as a potential therapeutic target to prevent lung adenocarcinoma.
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Affiliation(s)
- Weixuan Wang
- Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China
| | - Changmei Yang
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
| | - Haiteng Deng
- MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People's Republic of China
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Hunsu VO, Facey COB, Fields JZ, Boman BM. Retinoids as Chemo-Preventive and Molecular-Targeted Anti-Cancer Therapies. Int J Mol Sci 2021; 22:7731. [PMID: 34299349 PMCID: PMC8304138 DOI: 10.3390/ijms22147731] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
Retinoic acid (RA) agents possess anti-tumor activity through their ability to induce cellular differentiation. However, retinoids have not yet been translated into effective systemic treatments for most solid tumors. RA signaling is mediated by the following two nuclear retinoic receptor subtypes: the retinoic acid receptor (RAR) and the retinoic X receptor (RXR), and their isoforms. The identification of mutations in retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes. For example, chromosomal translocation involving RARA occurs in acute promyelocytic leukemia (APL), and all-trans retinoic acid (ATRA) is a highly effective and even curative therapeutic for APL patients. Thus, retinoid-based target discovery presents an important line of attack toward designing new, more effective strategies for treating other cancer types. Here, we review retinoid signaling, provide an update on retinoid agents and the current clinical research on retinoids in cancer, and discuss how the retinoid pathway genotype affects the ability of retinoid agents to inhibit the growth of colorectal cancer (CRC) cells. We also deliberate on why retinoid agents have not shown clinical efficacy against solid tumors and discuss alternative strategies that could overcome the lack of efficacy.
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Affiliation(s)
- Victoria O. Hunsu
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA
| | - Caroline O. B. Facey
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
| | | | - Bruce M. Boman
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA; (V.O.H.); (C.O.B.F.)
- Department of Biological Sciences, University of Delaware, Newark, DE 19713, USA
- Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA
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17
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Abás E, Bellés A, Rodríguez-Diéguez A, Laguna M, Grasa L. Selective cytotoxicity of cyclometalated gold(III) complexes on Caco-2 cells is mediated by G2/M cell cycle arrest. Metallomics 2021; 13:6296427. [PMID: 34114030 DOI: 10.1093/mtomcs/mfab034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/31/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022]
Abstract
New cyclometalated gold(III) complexes with a general structure [Au(C^N)(SR)2] or [Au(C^N)Cl(SR)], where C^N is a biphenyl ligand such as 2-(p-tolyl)pyridinate (tpy), 2-phenylpyridinate (ppy) and 2-benzylpyridinate (bzp) (SR = Spym, S(Me)2pym, 2-thiouracil (2-TU) and thiourea), and also with ethynyl moieties of the type [Au(C^N)(C≡C-Ar)2] (Ar = p-toluene and 2-pyridine) have been synthesized. All of them have been characterized, including X-ray studies of complex [Au(bzp)Cl(Spym)], and these studies have permitted to elucidate that leaving chloride ligand is trans located to CAr atom. After the full characterization, physicochemical properties were measured by evaluating drug-like water solubility and cell permeability (partition coefficient). All these experiments pointed that our complexes present adequate properties to be used as anticancer drugs. Although not all the complexes showed antiproliferative effects on Caco-2 cells, those that did were more cytotoxic than cisplatin; and complex [Au(tpy)Cl(2-TU)] is even more active than auranofin. In addition to this effectiveness, no evidence of cytotoxic effects was observed on considered normal cells (with the exception of [Au(bzp)Cl(2-TU)]. Further action mechanisms studies were performed using these selective complexes, showing cell cycle arrest on the G2/M phase, a proapoptotic behaviour and also the modification of some genes involved in tumorigenesis. Thus, as a result of this investigation, we present a new family of 17 cyclometalated complexes, 6 of them being selective and possible candidates to be used against colon cancer.
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Affiliation(s)
- Elisa Abás
- Instituto de Síntesis Química y Catálisis Homogénea, Universidad de Zaragoza-CSIC, Plaza S. Francisco s/n, 50009, Zaragoza, Spain
| | - Andrea Bellés
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain
| | - Antonio Rodríguez-Diéguez
- Departamento de Química Inorgánica, Facultad de Química, Universidad de Granada, Severo Ochoa s/n, 18071, Granada, Spain
| | - Mariano Laguna
- Instituto de Síntesis Química y Catálisis Homogénea, Universidad de Zaragoza-CSIC, Plaza S. Francisco s/n, 50009, Zaragoza, Spain
| | - Laura Grasa
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet, 177, 50013, Zaragoza, Spain.,Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain.,Instituto Agroalimentario de Aragón -IA2- (Universidad de Zaragoza-CITA), Zaragoza, Spain
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Yanardag S, Pugacheva EN. Primary Cilium Is Involved in Stem Cell Differentiation and Renewal through the Regulation of Multiple Signaling Pathways. Cells 2021; 10:1428. [PMID: 34201019 PMCID: PMC8226522 DOI: 10.3390/cells10061428] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/02/2021] [Accepted: 06/04/2021] [Indexed: 12/15/2022] Open
Abstract
Signaling networks guide stem cells during their lineage specification and terminal differentiation. Primary cilium, an antenna-like protrusion, directly or indirectly plays a significant role in this guidance. All stem cells characterized so far have primary cilia. They serve as entry- or check-points for various signaling events by controlling the signal transduction and stability. Thus, defects in the primary cilia formation or dynamics cause developmental and health problems, including but not limited to obesity, cardiovascular and renal anomalies, hearing and vision loss, and even cancers. In this review, we focus on the recent findings of how primary cilium controls various signaling pathways during stem cell differentiation and identify potential gaps in the field for future research.
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Affiliation(s)
- Sila Yanardag
- Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV 26506, USA;
| | - Elena N. Pugacheva
- Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV 26506, USA;
- West Virginia University Cancer Institute, School of Medicine, West Virginia University, Morgantown, WV 26506, USA
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19
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Tumor Suppressor Protein p53 and Inhibitor of Apoptosis Proteins in Colorectal Cancer-A Promising Signaling Network for Therapeutic Interventions. Cancers (Basel) 2021; 13:cancers13040624. [PMID: 33557398 PMCID: PMC7916307 DOI: 10.3390/cancers13040624] [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: 01/11/2021] [Revised: 01/30/2021] [Accepted: 02/01/2021] [Indexed: 02/08/2023] Open
Abstract
Simple Summary Tumor suppressor 53 (p53) is a multifunctional protein that regulates cell cycle, DNA repair, apoptosis and metabolic pathways. In colorectal cancer (CRC), mutations of the gene occur in 60% of patients and are associated with a more aggressive tumor phenotype and resistance to anti-cancer therapy. In addition, inhibitor of apoptosis (IAP) proteins are distinguished biomarkers overexpressed in CRC that impact on a diverse set of signaling pathways associated with the regulation of apoptosis/autophagy, cell migration, cell cycle and DNA damage response. As these mechanisms are further firmly controlled by p53, a transcriptional and post-translational regulation of IAPs by p53 is expected to occur in cancer cells. Here, we aim to review the molecular regulatory mechanisms between IAPs and p53 and discuss the therapeutic potential of targeting their interrelationship by multimodal treatment options. Abstract Despite recent advances in the treatment of colorectal cancer (CRC), patient’s individual response and clinical follow-up vary considerably with tumor intrinsic factors to contribute to an enhanced malignancy and therapy resistance. Among these markers, upregulation of members of the inhibitor of apoptosis protein (IAP) family effects on tumorigenesis and radiation- and chemo-resistance by multiple pathways, covering a hampered induction of apoptosis/autophagy, regulation of cell cycle progression and DNA damage response. These mechanisms are tightly controlled by the tumor suppressor p53 and thus transcriptional and post-translational regulation of IAPs by p53 is expected to occur in malignant cells. By this, cellular IAP1/2, X-linked IAP, Survivin, BRUCE and LIVIN expression/activity, as well as their intracellular localization is controlled by p53 in a direct or indirect manner via modulating a multitude of mechanisms. These cover, among others, transcriptional repression and the signal transducer and activator of transcription (STAT)3 pathway. In addition, p53 mutations contribute to deregulated IAP expression and resistance to therapy. This review aims at highlighting the mechanistic and clinical importance of IAP regulation by p53 in CRC and describing potential therapeutic strategies based on this interrelationship.
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Chatterjee R, Ghosh B, Mandal M, Nawn D, Banerjee S, Pal M, Paul RR, Banerjee S, Chatterjee J. Pathophysiological relationship between hypoxia associated oxidative stress, Epithelial-mesenchymal transition, stemness acquisition and alteration of Shh/ Gli-1 axis during oral sub-mucous fibrosis and oral squamous cell carcinoma. Eur J Cell Biol 2020; 100:151146. [PMID: 33418093 DOI: 10.1016/j.ejcb.2020.151146] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 12/08/2020] [Accepted: 12/16/2020] [Indexed: 02/07/2023] Open
Abstract
Oral sub-mucous fibrosis (OSF) is a pathophysiological state of oral cavity or oropharynx having a high chance of conversion to oral squamous cell carcinoma (OSCC). It involves fibrotic transformation of sub-epithelial matrix along with epithelial abnormalities. The present work aims to unveil the mechanistic domain regarding OSF to OSCC conversion exploring the scenario of hypoxia associated oxidative stress, epithelial-mesenchymal transition (EMT), metastasis and stemness acquisition. The study involves histopathological analysis of the diseased condition along with the exploration of oxidative stress status, assessment of mitochondrial condition, immunohistochemical analysis of HIF-1α, E-cadherin, vimentin, ERK, ALDH-1, CD133, Shh, Gli-1 and survivin expressions in the oral epithelial region together with the quantitative approach towards collagen deposition in the sub-epithelial matrix. Oxidative stress was found to be associated with type-II EMT in case of OSF attributing the development of sub-epithelial fibrosis and type-III EMT in case of OSCC favoring malignancy associated metastasis. Moreover, the acquisition of stemness during OSCC can also be correlated with EMT. Alteration of Shh and Gli-1 expression pattern revealed the mechanistic association of hypoxia with the phenotypic plasticity and disease manifestation in case of OSF as well as OSCC. Shh/ Gli-1 signaling can also be correlated with survivin mediated cytoprotective phenomenon under oxidative stress. Overall, the study established the correlative network of hypoxia associated oxidative stress, EMT and manifestation of oral pre-cancerous and cancerous condition in a holistic approach that may throw rays of hope in the therapeutic domain of the concerned diseases.
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Affiliation(s)
- Ritam Chatterjee
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India.
| | - Biswajoy Ghosh
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India
| | - Mousumi Mandal
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India
| | - Debaleena Nawn
- Advanced Technology Development Centre, Indian Institute of Technology, Kharagpur, West Bengal 721302, India
| | - Satarupa Banerjee
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India; School of Bioscience and Technology, Vellore Institute of Technology, Vellore, Tamilnadu 632014, India
| | - Mousumi Pal
- Guru Nanak Institute of Dental Sciences and Research, Kolkata 700114 West Bengal, India
| | - Ranjan Rashmi Paul
- Guru Nanak Institute of Dental Sciences and Research, Kolkata 700114 West Bengal, India
| | | | - Jyotirmoy Chatterjee
- School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal 721302, India
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21
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Lin Y, Zhong H, Sun B, Peng Y, Lu F, Chen M, Zhu M, Huang J. USP22 promotes proliferation in renal cell carcinoma by stabilizing survivin. Oncol Lett 2020; 20:246. [PMID: 32973959 DOI: 10.3892/ol.2020.12108] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 06/23/2020] [Indexed: 11/06/2022] Open
Abstract
Renal cell carcinoma (RCC) is one of the commonest urological tumors. The incidence of RCC ranks third among urological tumors, after prostate cancer and bladder tumors. However, the etiology of RCC remains unclear. Ubiquitin-specific protease 22 (USP22), a potential marker of cancer stem cells, is associated with the occurrence and progression of numerous tumors. However, the roles of USP22 in RCC have not yet been investigated. Survivin is a member of the inhibitor of apoptotic protein family involved in RCC progression. The present study first detected the expression of USP22 and survivin in RCC tissues using immunohistochemistry and western blotting. It was revealed that the protein levels of USP22 and survivin in RCC tissues were higher than those in adjacent normal renal tissue. Subsequently, it was demonstrated that USP22 knockdown inhibited the growth of an RCC cell line ACHN and downregulated the protein level of survivin, accompanied by an increased level of cleaved-caspase-3. By contrast, overexpression of USP22 promoted the growth of ACHN cells, upregulated the expression of survivin and decreased the level of cleaved-caspase-3. Notably, the changes in USP22 expression did not affect the SURVIVIN mRNA level. Finally, it was confirmed that USP22 interacted with survivin and stabilized it by downregulating its ubiquitination. The present results indicate that USP22 may regulate survivin via deubiquitination, thereby promoting the proliferation of RCC cells. The results of the current study suggest that USP22 may represent a novel therapeutic target for patients with RCC.
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Affiliation(s)
- Ying Lin
- Department of Nephrology, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
| | - Hongbin Zhong
- Department of Nephrology, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
| | - Baicheng Sun
- Department of Nephrology, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
| | - Yongtiao Peng
- Department of Nephrology, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
| | - Fuhua Lu
- Department of Nephrology, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
| | - Miaoxuan Chen
- Department of Nephrology, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
| | - Maoshu Zhu
- Central Laboratory, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
| | - Jiyi Huang
- Department of Nephrology, The Fifth Hospital of Xiamen, Xiamen, Fujian 361003, P.R. China
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22
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Silva-Pavez E, Tapia JC. Protein Kinase CK2 in Cancer Energetics. Front Oncol 2020; 10:893. [PMID: 32626654 PMCID: PMC7315807 DOI: 10.3389/fonc.2020.00893] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/06/2020] [Indexed: 12/15/2022] Open
Abstract
Protein kinase CK2 (formerly known as casein kinase 2) is abnormally elevated in many cancers. This may increase tumor aggressiveness through CK2-dependent phosphorylation of key proteins in several signaling pathways. In this work, we have compiled evidence from the literature to suggest that CK2 also modulates a metabolic switch characteristic of cancer cells that enhances resistance to death, due to either drugs or to a microenvironment deficient in oxygen or nutrients. Concurrently, CK2 may help to preserve mitochondrial activity in a PTEN-dependent manner. PTEN, widely recognized as a tumor suppressor, is another CK2 substrate in the PI3K/Akt signaling pathway that promotes cancer viability and aerobic glycolysis. Given that CK2 can regulate Akt as well as two of its main effectors, namely mTORC1 and β-catenin, we comprehensively describe how CK2 may modulate cancer energetics by regulating expression of key targets and downstream processes, such as HIF-1 and autophagy, respectively. Thus, the specific inhibition of CK2 may lead to a catastrophic death of cancer cells, which could become a feasible therapeutic strategy to beat this devastating disease. In fact, ATP-competitive inhibitors, synthetic peptides and antisense oligonucleotides have been designed as CK2 inhibitors, some of them used in preclinical models of cancer, of which TBB and silmitasertib are widely known. We will finish by discussing a hypothetical scenario in which cancer cells are "addicted" to CK2; i.e., in which many proteins that regulate signaling pathways and metabolism-linked processes are highly dependent on this kinase.
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Affiliation(s)
- Eduardo Silva-Pavez
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Julio C Tapia
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
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23
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APC gene 3'UTR SNPs and interactions with environmental factors are correlated with risk of colorectal cancer in Chinese Han population. Biosci Rep 2020; 40:222328. [PMID: 32159210 PMCID: PMC7087318 DOI: 10.1042/bsr20192429] [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: 07/13/2019] [Revised: 02/19/2020] [Accepted: 03/03/2020] [Indexed: 11/29/2022] Open
Abstract
Objective: To study the correlation between adenomatous polyposis coli (APC) gene 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) and their interactions with environmental factors and the risk of colorectal cancer (CRC) in a Chinese Han population. Methods: Genotypes of APC gene 3′UTR rs1804197, rs41116, rs448475, and rs397768 loci in 340 Chinese Han patients with CRC and 340 healthy controls were analyzed. All patients with CRC were analyzed for progression-free survival (PFS) during a 3-year follow-up. Results: The risk of CRC in subjects carrying the APC gene rs1804197 A allele was 2.95-times higher than for the C allele carriers. The interactions of the rs1804197 SNP with body mass index (BMI) and smoking were associated with the risk of CRC. The risk of CRC in the APC gene rs397768 G allele carriers was 1.68-times higher than in the A allele carriers. The interaction between the rs397768 locus SNP and gender was also associated with the risk of CRC. The 3-year PFS of patients with APC gene rs1804197 AA genotype, CA genotype, and CC genotype CRC decreased in this order, with significant difference. In addition, the 3-year PFS of rs397768 locus GG genotype, AG genotype, and AA genotype CRC patients decreased in this order, and the difference was significant. Conclusion: The rs1804197 locus in the 3′UTR region of the APC gene and its interactions with BMI and smoking are associated with the risk of CRC in a Chinese Han population. In addition, the interaction between rs397768 locus SNP and gender is related to the risk of CRC.
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Obatoclax, a Pan-BCL-2 Inhibitor, Downregulates Survivin to Induce Apoptosis in Human Colorectal Carcinoma Cells Via Suppressing WNT/β-catenin Signaling. Int J Mol Sci 2020; 21:ijms21051773. [PMID: 32150830 PMCID: PMC7084590 DOI: 10.3390/ijms21051773] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 02/27/2020] [Accepted: 03/03/2020] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is a highly prevailing cancer and the fourth leading cause of cancer mortality worldwide. Aberrant expression of antiapoptotic BCL-2 family proteins is closely linked to neoplastic progression and chemoresistance. Obatoclax is a clinically developed drug, which binds antiapoptotic BCL-2, BCL-xL, and MCL-1 for inhibition to elicit apoptosis. Survivin is an antiapoptotic protein, whose upregulation correlates with pathogenesis, therapeutic resistance, and poor prognosis in CRC. Herein, we provide the first evidence delineating the functional linkage between Obatoclax and survivin in the context of human CRC cells. In detail, Obatoclax was found to markedly downregulate survivin. This downregulation was mainly achieved via transcriptional repression, as Obatoclax lowered the levels of both survivin mRNA and promoter activity, while blocking proteasomal degradation failed to prevent survivin from downregulation by Obatoclax. Notably, ectopic survivin expression curtailed Obatoclax-induced apoptosis and cytotoxicity, confirming an essential role of survivin downregulation in Obatoclax-elicited anti-CRC effect. Moreover, Obatoclax was found to repress hyperactive WNT/β-catenin signaling activity commonly present in human CRC cells, and, markedly, ectopic expression of dominant-active β-catenin mutant rescued the levels of survivin along with elevated cell viability. We further revealed that, depending on the cell context, Obatoclax suppresses WNT/β-catenin signaling in HCT 116 cells likely via inducing β-catenin destabilization, or by downregulating LEF1 in DLD-1 cells. Collectively, we for the first time define survivin downregulation as a novel, pro-apoptotic mechanism of Obatoclax as a consequence of Obatocalx acting as an antagonist to WNT/β-catenin signaling.
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25
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Deng J, Hua L, Han T, Tian M, Wang D, Tang H, Sun S, Chen H, Cheng H, Zhang T, Xie Q, Wan L, Zhu H, Gong Y. The CREB-binding protein inhibitor ICG-001: a promising therapeutic strategy in sporadic meningioma with NF2 mutations. Neurooncol Adv 2020; 2:vdz055. [PMID: 32642722 PMCID: PMC7212891 DOI: 10.1093/noajnl/vdz055] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background Meningiomas with Neurofibromin 2 gene mutations (NF2-mutant meningiomas) account for ~40% of the sporadic meningiomas. However, there is still no effective drug treatment for the disease. Methods Expression profile of Merlin protein was explored through immunohistochemistry in a meningioma patient cohort (n = 346). A 20-agent library covering a wide range of meningioma relevant targets was tested using meningioma cell lines IOMM-Lee (NF2 wildtype) and CH157-MN (NF2 deficient). Therapeutic effects and biological mechanisms of the identified compound, ICG-001, in NF2-mutant meningiomas were further characterized in vitro and in patient-derived xenograft (PDX) models. Results Low Merlin expression was associated with meningioma proliferation and poor clinical outcomes in a large patient series. ICG-001, a cAMP-responsive element binding (CREB)-binding protein (CBP) inhibitor, selectively suppressed tumor growth of cells with low Merlin expression. Besides, ICG-001 mediated CH157-MN and IOMM-Lee growth inhibition primarily through robust induction of the G1 cell-cycle arrest. Treatment with ICG-001 alone significantly reduced the growth of NF2-mutant xenografts in mice, as well. We also provide further evidence that ICG-001 inhibits proliferation of NF2-mutant meningioma cells at least partly through attenuating the FOXM1-mediated Wnt/β-catenin signaling. Conclusions This study highlights the importance of ligand-mediated Wnt/β-catenin signaling as well as its drugable potency in NF2-mutant meningioma.
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Affiliation(s)
- Jiaojiao Deng
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lingyang Hua
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tao Han
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Mi Tian
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Daijun Wang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hailiang Tang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shuchen Sun
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hong Chen
- Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Haixia Cheng
- Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Tao Zhang
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Qing Xie
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lixin Wan
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Hongda Zhu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ye Gong
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China
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Liu E, Zhou Q, Xie AJ, Li X, Li M, Ye J, Li S, Ke D, Wang Q, Xu ZP, Li L, Yang Y, Liu GP, Wang XC, Li HL, Wang JZ. Tau acetylates and stabilizes β-catenin thereby promoting cell survival. EMBO Rep 2020; 21:e48328. [PMID: 31930681 DOI: 10.15252/embr.201948328] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 11/30/2019] [Accepted: 12/11/2019] [Indexed: 12/19/2022] Open
Abstract
Overexpressing Tau counteracts apoptosis and increases dephosphorylated β-catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate β-catenin at K49 in a concentration-, time-, and pH-dependent manner. β-catenin K49 acetylation inhibits its phosphorylation and its ubiquitination-associated proteolysis, thus increasing β-catenin protein levels. K49 acetylation further promotes nuclear translocation and the transcriptional activity of β-catenin, and increases the expression of survival-promoting genes (bcl2 and survivin), counteracting apoptosis. Mutation of Tau's acetyltransferase domain or co-expressing non-acetylatable β-catenin-K49R prevents increased β-catenin signaling and abolishes the anti-apoptotic function of Tau. Our data reveal that Tau preserves β-catenin by acetylating K49, and upregulated β-catenin/survival signaling in turn mediates the anti-apoptotic effect of Tau.
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Affiliation(s)
- Enjie Liu
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qiuzhi Zhou
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ao-Ji Xie
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoguang Li
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengzhu Li
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinwang Ye
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shihong Li
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Ke
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qun Wang
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi-Peng Xu
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Li
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Yang
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gong-Ping Liu
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Chuan Wang
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong-Lian Li
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Zhi Wang
- Key Laboratory of Ministry of Education of China for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
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27
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Allam RM, El-Halawany AM, Al-Abd AM. Chemo-sensitizing agents from natural origin for colorectal cancer: Pharmacodynamic and cellular pharmacokinetics approaches. DRUG RESISTANCE IN COLORECTAL CANCER: MOLECULAR MECHANISMS AND THERAPEUTIC STRATEGIES 2020:93-116. [DOI: 10.1016/b978-0-12-819937-4.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Abstract
Colorectal cancer (CRC) is a common cancer globally. It is a complex disease influenced by genetic and environmental factors. Early studies on familial cases have identified major genes involved in CRC, such as proto-oncogenes KRAS, PIK3CA and BRAF, and tumour-suppressor genes APC and TP53. These genes have provided valuable insight into the molecular pathogenesis of CRC, and some have made ways to clinical utility to help diagnose cancer syndromes, prognosticate oncological outcomes and predict treatment responses. While these genetic factors are important, recent studies have suggested contribution of microorganisms to colorectal carcinogenesis. Observational studies, animal experiments and translational works have identified several microorganisms as potential carcinogenic bacteria, such as Fusobacterium nucleatum and Peptostreptococcus anaerobius. With the advent of sequencing technology and bioinformatics, more genomic and metagenomic factors are being uncovered as important players in CRC carcinogenesis. This article aims to review recent genomic and metagenomic discoveries relating to CRC.
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Affiliation(s)
- Charmaine Ng
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Haojun Li
- Li Ka Shing Institute of Health Science, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - William K K Wu
- Li Ka Shing Institute of Health Science, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Sunny H Wong
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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29
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Abe T, Amaike Y, Shizu R, Takahashi M, Kano M, Hosaka T, Sasaki T, Kodama S, Matsuzawa A, Yoshinari K. Role of YAP Activation in Nuclear Receptor CAR-Mediated Proliferation of Mouse Hepatocytes. Toxicol Sci 2019; 165:408-419. [PMID: 29893953 DOI: 10.1093/toxsci/kfy149] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEA domain family member (TEAD). In mouse livers, 1,4-bis-(2-[3,5-dichloropyridyloxy])benzene (TCPOBOP) (a mouse CAR [mCAR] activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them. Furthermore, in cell-based reporter gene assays, CAR activation enhanced the YAP/TEAD-dependent transcription. To investigate the role of YAP/TEAD activation in the CAR-dependent hepatocyte proliferation, we sought to establish an in vitro system completely reproducing CAR-dependent cell proliferation. Since CAR was only slightly expressed in cultured mouse primary hepatocytes compared with mouse livers and no proliferation was observed after treatment with TCPOBOP, we overexpressed CAR using mCAR expressing adenovirus (Ad-mCAR-V5) in mouse primary hepatocytes. Ad-mCAR-V5 infection and TCPOBOP treatment induced hepatocyte proliferation. Similar results were obtained with immortalized normal mouse hepatocytes as well. In the established in vitro system, CAR-dependent proliferation was strongly inhibited by Yap knockdown and completely abolished by verteporfin treatment. Our present results obtained in in vivo and in vitro experiments suggest that YAP/TEAD activation plays key roles in CAR-dependent proliferation of murine hepatocytes.
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Affiliation(s)
- Taiki Abe
- Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.,Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan.,Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
| | - Yuto Amaike
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
| | - Ryota Shizu
- Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.,Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
| | - Miki Takahashi
- Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.,Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
| | - Makoto Kano
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
| | - Takuomi Hosaka
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
| | - Takamitsu Sasaki
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan
| | - Susumu Kodama
- Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
| | - Atsushi Matsuzawa
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
| | - Kouichi Yoshinari
- Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.,Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan.,Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
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30
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Abbaszadeh H, Valizadeh A, Mahdavinia M, Teimoori A, Pipelzadeh MH, Zeidooni L, Alboghobeish S. 3-Bromopyruvate potentiates TRAIL-induced apoptosis in human colon cancer cells through a reactive oxygen species- and caspase-dependent mitochondrial pathway. Can J Physiol Pharmacol 2019; 97:1176-1184. [PMID: 31491344 DOI: 10.1139/cjpp-2019-0131] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising anticancer cytokine with minimal toxicity towards normal cells. Nevertheless, most primary cancers are often intrinsically TRAIL-resistant or can acquire resistance after TRAIL therapy. This study aimed to investigate the inhibitory effect of co-treatment of 3-bromopyruvate (3-BP) as a potent anticancer agent with TRAIL on colon cancer cells (HT-29). The results of present study indicated that combined treatment with 3-BP and TRAIL inhibited the proliferation of HT-29 cells to a greater extent (88.4%) compared with 3-BP (54%) or TRAIL (11%) treatment alone. In contrast, the combination of 3-BP and TRAIL had no significant inhibitory effect on the proliferation of normal cells (HEK-293) (8.4%). At a cellular mechanistic level, the present study showed that 3-BP sensitized human colon cancer cells to TRAIL-induced apoptosis via reactive oxygen species generation, upregulation of Bax, downregulation of Bcl-2 and survivin, release of cytochrome c into the cytosol, and activation of caspase-3. In normal cells, 3-BP, TRAIL, or combination of both had no significant effect on the reactive oxygen species levels, release of cytochrome c, and caspase-3 activity. Therefore, the combination of 3-BP and TRAIL can be a promising therapeutic strategy for treatment of colon cancer.
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Affiliation(s)
- Hassan Abbaszadeh
- Department of Pharmacology, School of Pharmacy, Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Armita Valizadeh
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masoud Mahdavinia
- Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Teimoori
- Department of Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Hassan Pipelzadeh
- Department of Pharmacology, School of Pharmacy, Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Leila Zeidooni
- Department of Toxicology, School of Pharmacy, Student Research Committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Soheila Alboghobeish
- Department of Pharmacology, School of Medicine, Student Research Committee of Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Khare V, Tabassum S, Chatterjee U, Chatterjee S, Ghosh MK. RNA helicase p68 deploys β-catenin in regulating RelA/p65 gene expression: implications in colon cancer. J Exp Clin Cancer Res 2019; 38:330. [PMID: 31351496 PMCID: PMC6660689 DOI: 10.1186/s13046-019-1304-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 06/30/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND RelA/p65 a crucial member of NF-κB signaling pathway plays diverse role in mediating oncogenesis. Limited knowledge prevails on the mechanistic insights of RelA gene regulation. RNA helicase p68 apart from being a vital player of RNA metabolism acts as a transcriptional coactivator of several oncogenic transcription factors including β-catenin and is highly implicated in cancer progression. In this study, we aim to discern the molecular mechanism of how an RNA helicase, p68 deploys a major oncogenic signaling pathway, Wnt/ β-catenin to regulate the expression of RelA, an indispensable component of NF-κB signaling pathway towards driving colon carcinogenesis. METHODS Immunoblotting and quantitative RT-PCR was performed for determining the protein and mRNA expressions of the concerned genes respectively. Luciferase assay was employed for studying the promoter activity of RelA. Chromatin immunoprecipitation was used to evaluate the occupancy of transcription factors on the RelA promoter. Immunohistochemical analysis was conducted using FFPE sections derived from normal human colon and colon cancer patient samples. Finally, a syngeneic colorectal allograft mouse model was used to assess physiological significance of the in vitro findings. RESULTS p68, β-catenin and RelA proteins were found to bear strong positive correlation in normal and colon carcinoma patient samples. Both p68 and β-catenin increased RelA mRNA and protein expression. p68, β-catenin and Wnt3a elevated RelA promoter activity. Conversely, p68 and β-catenin knockdown diminished RelA promoter activity and led to reduced RelA mRNA and protein expression. p68 was perceived to occupy RelA promoter with β-catenin at the TCF4/LEF (TBE) sites thereby potentiating RelA transcription. p68 and β-catenin alliance positively modulated the expression of signature NF-κB target genes. Enhanced NF-κB target gene expression by p68 was corroborated by findings in clinical samples. Tumors generated in mice colorectal allograft model, stably expressing p68 further reinforced our in vitro findings. CONCLUSIONS We report for the first time a novel mechanism of alliance between p68 and β-catenin in regulating the expression of RelA and stimulating the NF-κB signaling axis towards driving colon carcinogenesis. This study unravels novel modes of p68-mediated colon carcinogenesis, marking it a potential target for therapy.
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Affiliation(s)
- Veenita Khare
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032 India
| | - Shaheda Tabassum
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032 India
| | - Uttara Chatterjee
- Division of Pathology, Park Clinic, 4, Gorky Terrace, Kolkata, 700017 India
| | - Sandip Chatterjee
- Division of Pathology, Park Clinic, 4, Gorky Terrace, Kolkata, 700017 India
| | - Mrinal K. Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032 India
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Milczarek M, Rossowska J, Klopotowska D, Stachowicz M, Kutner A, Wietrzyk J. Tacalcitol increases the sensitivity of colorectal cancer cells to 5-fluorouracil by downregulating the thymidylate synthase. J Steroid Biochem Mol Biol 2019; 190:139-151. [PMID: 30923017 DOI: 10.1016/j.jsbmb.2019.03.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 03/20/2019] [Accepted: 03/23/2019] [Indexed: 12/18/2022]
Abstract
5-Fluorouracil (5-FU) is an anticancer drug that is most frequently used to treat colorectal cancer (CRC) patients, but unfortunately it shows limited efficacy. We recently demonstrated that vitamin D analogs (VDAs), particularly tacalcitol (coded as PRI-2191), potentiate its anticancer activity in an in vivo mouse and human CRC model. The purpose of this study was to explain the mechanism underlying the enhancement of 5-FU efficacy by PRI-2191 towards human HT-29 CRC cells. We showed that PRI-2191 induces the CDKN1A (gene encoding p21Waf1/Cip1) expression directly through vitamin D receptor (VDR) in a p53-independent manner and thus decreases the thymidylate synthase expression both at the mRNA and protein level. It is the main mechanism by which PRI-2191 improves the anticancer efficacy of 5-FU towards HT-29 cells. Additionally, we indicated that the VDR also participates in 5-FU mechanism of action. 5-FU significantly increased TYMS (gene encoding thymidylate synthase (TS)) and BIRC5 (gene encoding survivin) level in HT-29 cells with silenced VDR. Furthermore, PRI-2191 induced E-cadherin and ZO-1 expression and thus reduced the level of BIRC5 in HT-29 cells. The induction of E-cadherin expression may also contribute to the reduction of c-Myc level and consequently the downregulation of TS. Our results also indicate that calcium-sensing receptor (CaSR) plays a role in the activity of PRI-2191 but has no influence on the 5-FU mechanism of action. In conclusion, we suggest that both VDR and CaSR might be useful as molecular markers for predicting treatment outcomes and identifying the CRC patient subgroups who might benefit from 5-FU-based chemotherapy combined with vitamin D analog.
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Affiliation(s)
- Magdalena Milczarek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland.
| | - Joanna Rossowska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
| | - Dagmara Klopotowska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
| | - Martyna Stachowicz
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
| | - Andrzej Kutner
- Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, 1 Banacha, 02-097, Warsaw, Poland
| | - Joanna Wietrzyk
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 12 Rudolfa Weigla, 53-114, Wroclaw, Poland
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Ismail NI, Othman I, Abas F, H Lajis N, Naidu R. Mechanism of Apoptosis Induced by Curcumin in Colorectal Cancer. Int J Mol Sci 2019; 20:E2454. [PMID: 31108984 PMCID: PMC6566943 DOI: 10.3390/ijms20102454] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 04/20/2019] [Accepted: 04/26/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is among the top three cancer with higher incident and mortality rate worldwide. It is estimated that about over than 1.1 million of death and 2.2 million new cases by the year 2030. The current treatment modalities with the usage of chemo drugs such as FOLFOX and FOLFIRI, surgery and radiotherapy, which are usually accompanied with major side effects, are rarely cured along with poor survival rate and at higher recurrence outcome. This trigger the needs of exploring new natural compounds with anti-cancer properties which possess fewer side effects. Curcumin, a common spice used in ancient medicine was found to induce apoptosis by targeting various molecules and signaling pathways involved in CRC. Disruption of the homeostatic balance between cell proliferation and apoptosis could be one of the promoting factors in colorectal cancer progression. In this review, we describe the current knowledge of apoptosis regulation by curcumin in CRC with regard to molecular targets and associated signaling pathways.
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Affiliation(s)
- Nor Isnida Ismail
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway Darul Ehsan, Malaysia.
- UniKL MESTECH, A1-1 Jalan TKS1, Taman Kajang Sentral, 43000 Kajang, Malaysia.
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway Darul Ehsan, Malaysia.
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, University Putra Malaysia, UPM, 43400 Serdang, Malaysia.
- Department of Food Science, Faculty of Food Science and Technology, University Putra Malaysia, UPM, 434000 Serdang, Malaysia.
| | - Nordin H Lajis
- Laboratory of Natural Products, Faculty of Science, University Putra Malaysia, UPM, 43400 Serdang, Malaysia.
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway Darul Ehsan, Malaysia.
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Shah SC, Glass J, Giustino G, Hove JRT, Castaneda D, Torres J, Kumar A, Elman J, Ullman TA, Itzkowitz SH. Statin Exposure Is Not Associated with Reduced Prevalence of Colorectal Neoplasia in Patients with Inflammatory Bowel Disease. Gut Liver 2019; 13:54-61. [PMID: 30400722 PMCID: PMC6346999 DOI: 10.5009/gnl18178] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/29/2018] [Accepted: 07/07/2018] [Indexed: 12/21/2022] Open
Abstract
Background/Aims Statins have been postulated to lower the risk of colorectal neoplasia. No studies have examined any possible chemopreventive effect of statins in patients with inflammatory bowel disease (IBD) undergoing colorectal cancer (CRC) surveillance. This study examined the association of statin exposure with dysplasia and CRC in patients with IBD undergoing dysplasia surveillance colonoscopies. Methods A cohort of patients with IBD undergoing colonoscopic surveillance for dysplasia and CRC at a single academic medical center were studied. The inclusion criteria were IBD involving the colon for 8 years (or any colitis duration if associated with primary sclerosing cholangitis [PSC]) and at least two colonoscopic surveillance exams. The exclusion criteria were CRC or high-grade dysplasia (HGD) prior to or at enrollment, prior colectomy, or limited (<30%) colonic disease. The primary outcome was the frequency of dysplasia and/or CRC in statin-exposed versus nonexposed patients. Results A total of 642 patients met the inclusion criteria (57 statin-exposed and 585 nonexposed). The statin-exposed group had a longer IBD duration, longer follow-up period, and more colonoscopies but lower inflammatory scores, less frequent PSC and less use of thiopurines and biologics. There were no differences in low-grade dysplasia, HGD, or CRC development during the follow-up period between the statin-exposed and nonexposed groups (21.1%, 5.3%, 1.8% vs 19.2%, 2.9%, 2.9%, respectively). Propensity score analysis did not alter the overall findings. Conclusions In IBD patients undergoing surveillance colonoscopies, statin use was not associated with reduced dysplasia or CRC rates. The role of statins as chemopreventive agents in IBD remains controversial.
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Affiliation(s)
- Shailja C Shah
- Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.,The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jason Glass
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gennaro Giustino
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joren R Ten Hove
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Daniel Castaneda
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joana Torres
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Gastroenterology, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Akash Kumar
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jordan Elman
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Thomas A Ullman
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven H Itzkowitz
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Luong-Gardiol N, Siddiqui I, Pizzitola I, Jeevan-Raj B, Charmoy M, Huang Y, Irmisch A, Curtet S, Angelov GS, Danilo M, Juilland M, Bornhauser B, Thome M, Hantschel O, Chalandon Y, Cazzaniga G, Bourquin JP, Huelsken J, Held W. γ-Catenin-Dependent Signals Maintain BCR-ABL1 + B Cell Acute Lymphoblastic Leukemia. Cancer Cell 2019; 35:649-663.e10. [PMID: 30991025 DOI: 10.1016/j.ccell.2019.03.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 01/29/2019] [Accepted: 03/14/2019] [Indexed: 11/23/2022]
Abstract
The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1+ B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1+ B-ALL.
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Affiliation(s)
- Noemie Luong-Gardiol
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Imran Siddiqui
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Irene Pizzitola
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Beena Jeevan-Raj
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Mélanie Charmoy
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Yun Huang
- Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland
| | - Anja Irmisch
- Swiss Institute for Experimental Cancer Research (ISREC), Federal University of Technology Lausanne (EPFL), Lausanne, Switzerland
| | - Sara Curtet
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Georgi S Angelov
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Maxime Danilo
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland
| | - Mélanie Juilland
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Beat Bornhauser
- Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland
| | - Margot Thome
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Oliver Hantschel
- Swiss Institute for Experimental Cancer Research (ISREC), Federal University of Technology Lausanne (EPFL), Lausanne, Switzerland
| | - Yves Chalandon
- Service d'Hématologie, Hôpitaux Universitaire de Genève, Geneva, Switzerland
| | - Gianni Cazzaniga
- Centro Ricerca Tettamanti, Pediatric Clinic University of Milano-Bicocca, Monza, Italy
| | - Jean-Pierre Bourquin
- Department of Pediatric Oncology and Children's Research Centre, University Children's Hospital Zürich, Zürich, Switzerland
| | - Joerg Huelsken
- Swiss Institute for Experimental Cancer Research (ISREC), Federal University of Technology Lausanne (EPFL), Lausanne, Switzerland
| | - Werner Held
- Department of Oncology UNIL CHUV, University of Lausanne, Epalinges, Switzerland.
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Kamra M, Maiti B, Dixit A, Karande AA, Bhattacharya S. Tumor Chemosensitization through Oncogene Knockdown Mediated by Unique α-Tocopherylated Cationic Geminis. Biomacromolecules 2019; 20:1555-1566. [DOI: 10.1021/acs.biomac.8b01751] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Mohini Kamra
- Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
| | - Bappa Maiti
- Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
- School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Kolkata 700 032, India
| | - Akanksha Dixit
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Anjali A. Karande
- Department of Biochemistry, Indian Institute of Science, Bangalore 560012, India
| | - Santanu Bhattacharya
- Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
- School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, Kolkata 700 032, India
- Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India
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Poynter L, Galea D, Veselkov K, Mirnezami A, Kinross J, Nicholson J, Takáts Z, Darzi A, Mirnezami R. Network Mapping of Molecular Biomarkers Influencing Radiation Response in Rectal Cancer. Clin Colorectal Cancer 2019; 18:e210-e222. [PMID: 30928329 DOI: 10.1016/j.clcc.2019.01.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 11/12/2018] [Accepted: 01/23/2019] [Indexed: 02/07/2023]
Abstract
Preoperative radiotherapy (RT) plays an important role in the management of locally advanced rectal cancer (RC). Tumor regression after RT shows marked variability, and robust molecular methods are needed to help predict likely response. The aim of this study was to review the current published literature and use Gene Ontology (GO) analysis to define key molecular biomarkers governing radiation response in RC. A systematic review of electronic bibliographic databases (Medline, Embase) was performed for original articles published between 2000 and 2015. Biomarkers were then classified according to biological function and incorporated into a hierarchical GO tree. Both significant and nonsignificant results were included in the analysis. Significance was binarized on the basis of univariate and multivariate statistics. Significance scores were calculated for each biological domain (or node), and a direct acyclic graph was generated for intuitive mapping of biological pathways and markers involved in RC radiation response. Seventy-two individual biomarkers across 74 studies were identified. On highest-order classification, molecular biomarkers falling within the domains of response to stress, cellular metabolism, and pathways inhibiting apoptosis were found to be the most influential in predicting radiosensitivity. Homogenizing biomarker data from original articles using controlled GO terminology demonstrated that cellular mechanisms of response to RT in RC-in particular the metabolic response to RT-may hold promise in developing radiotherapeutic biomarkers to help predict, and in the future modulate, radiation response.
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Affiliation(s)
- Liam Poynter
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Dieter Galea
- Computational & Systems Medicine, Imperial College London, London, UK
| | - Kirill Veselkov
- Computational & Systems Medicine, Imperial College London, London, UK
| | | | - James Kinross
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Jeremy Nicholson
- Computational & Systems Medicine, Imperial College London, London, UK
| | - Zoltán Takáts
- Computational & Systems Medicine, Imperial College London, London, UK
| | - Ara Darzi
- Department of Surgery & Cancer, Imperial College London, London, UK
| | - Reza Mirnezami
- Department of Surgery & Cancer, Imperial College London, London, UK; St Mark's Hospital and Academic Institute, Harrow, London, UK.
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Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling. Apoptosis 2019; 24:326-340. [DOI: 10.1007/s10495-019-01519-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Boozari M, Nejad Ebrahimi S, Soltani S, Tayarani-Najaran Z, Emami SA, Asili J, Iranshahi M. Absolute configuration and anti-cancer effect of prenylated flavonoids and flavonostilbenes from Sophora pachycarpa: Possible involvement of Wnt signaling pathway. Bioorg Chem 2019; 85:498-504. [PMID: 30802806 DOI: 10.1016/j.bioorg.2019.01.051] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 12/24/2018] [Accepted: 01/25/2019] [Indexed: 12/12/2022]
Abstract
A new prenylated flavonostilbene, namely, alopecurone P together with three known compounds sophoraflavanone G, 2-(4-hydroxyphenyl)-2,3-dihydrobenzo[b]furan-3,4,6-triol and alopecurone J were characterized from the roots of Sophora pachycarpa. The absolute configuration of alopecurones J and P were characterized by comparison of experimental electronic circular dichroism (ECD) spectroscopy and simulated data using time-dependent density functional theory (TDDFT) for possible stereoisomers. The cytotoxic properties of isolated compounds have also been evaluated on two breast cancer cell lines (MCF-7 and MDA-MB-231) and normal cell line (NIH/3T3) using AlamarBlue®, flowcytometry and western blot assays. Alopecurone J and P showed cytotoxic effect on MCF-7 cell line through Wnt signaling pathway. It seems that the presence of lavandulyl substitution in C-8 position of flavanone structure increased the cytotoxic effect.
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Affiliation(s)
- Motahare Boozari
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samad Nejad Ebrahimi
- Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G.C., Evin, Tehran, Iran
| | - Saba Soltani
- Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Tayarani-Najaran
- Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Ahmad Emami
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Javad Asili
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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40
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Martínez-García D, Manero-Rupérez N, Quesada R, Korrodi-Gregório L, Soto-Cerrato V. Therapeutic strategies involving survivin inhibition in cancer. Med Res Rev 2018; 39:887-909. [PMID: 30421440 DOI: 10.1002/med.21547] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 09/13/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023]
Abstract
Survivin is a small protein that belongs to the inhibitor of apoptosis protein family. It is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor prognosis in many human neoplasms. This apoptotic inhibitor has a relevant role in both the promotion of cancer cell survival and in the inhibition of cell death. Consequently, aberrant survivin expression stimulates tumor progression and confers resistance to several therapeutic strategies in a variety of tumors. In fact, efficient survivin downregulation or inhibition results in spontaneous apoptosis or sensitization to chemotherapy and radiotherapy. Therefore, all these features make survivin an attractive therapeutic target to treat cancer. Currently, there are several survivin inhibitors under clinical evaluation, although more specific and efficient survivin inhibitors are being developed. Moreover, novel combination regimens targeting survivin together with other therapeutic approaches are currently being designed and assessed. In this review, recent progress in the therapeutic options targeting survivin for cancer treatment is analyzed. Direct survivin inhibitors and their current development status are explored. Besides, the major signaling pathways implicated in survivin regulation are described and different therapeutic approaches involving survivin indirect inhibition are evaluated. Finally, promising novel inhibitors under preclinical or clinical evaluation as well as challenges of developing survivin inhibitors as a new therapy for cancer treatment are discussed.
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Affiliation(s)
- David Martínez-García
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Noemí Manero-Rupérez
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Hospital del Mar Medical Research Institute, Barcelona Biomedical Research Park, Barcelona, Spain
| | - Roberto Quesada
- Department of Chemistry, Universidad de Burgos, Burgos, Spain
| | - Luís Korrodi-Gregório
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Vanessa Soto-Cerrato
- Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
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Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells. Cell Death Dis 2018; 9:1050. [PMID: 30323195 PMCID: PMC6189045 DOI: 10.1038/s41419-018-1083-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 07/31/2018] [Accepted: 08/20/2018] [Indexed: 12/20/2022]
Abstract
Mitochondrial morphology is remodeled by continuous dynamic cycles of fission and fusion. Emerging data have shown that the disturbance of balance between mitochondrial fission and fusion is involved in the progression of several types of neoplasms. However, the status of mitochondrial dynamics and its potential biological roles in breast cancer (BC), particularly in triple negative BC (TNBC) are not fully clear. Here, we reported that the mitochondrial fission was significantly increased in BC tissues, especially in the TNBC tissues, when compared with that in the corresponding peritumor tissues. Meanwhile, our data showed that Drp1 was upregulated, while Mfn1 was downregulated in TNBC. Moreover, elevated mitochondrial fission was associated with poorer prognosis in TNBC patients. Mitochondrial fission promoted the survival of TNBC cells both in vitro and in vivo. Furthermore, we identified a positive feedback loop between mitochondrial fission and Notch signaling pathway in TNBC cells, as proved by the experimental evidence that the activation of Notch signaling enhanced Drp1-mediated mitochondrial fission and Drp1-mediated mitochondrial fission in turn promoted the activation of Notch signaling, which ultimately promoted the cell survival of TNBC via increasing survivin expression level. Inhibition of either Notch1 or Drp1 significantly impaired the activation of the other, leading to the suppression of TNBC cell survival and proliferation. Collectively, our data reveal a novel mechanism that the positive feedback loop between mitochondrial fission and Notch signaling promotes the survival, proliferation and apoptotic resistance of TNBC cells via increasing survivin expression and thus favors cancer progression.
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Forouzesh F, Agharezaee N. Review on the molecular signaling pathways involved in controlling cancer stem cells and treatment. THE JOURNAL OF QAZVIN UNIVERSITY OF MEDICAL SCIENCES 2018. [DOI: 10.29252/qums.22.3.77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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Moradi Marjaneh R, Hassanian SM, Ghobadi N, Ferns GA, Karimi A, Jazayeri MH, Nasiri M, Avan A, Khazaei M. Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer. J Cell Physiol 2018; 233:6538-6549. [DOI: 10.1002/jcp.26640] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 03/30/2018] [Indexed: 12/25/2022]
Affiliation(s)
- Reyhaneh Moradi Marjaneh
- Department of Physiology, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center Mashhad University of Medical Sciences Mashhad Iran
- Department of Medical Biochemistry, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
- Microanatomy Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Niloofar Ghobadi
- Metabolic Syndrome Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Gordon A. Ferns
- Brighton & Sussex Medical School Division of Medical Education Falmer, Brighton, Sussex UK
| | - Afshin Karimi
- Quality Department of Nutricia Mashhad Mild Powder Industrial Mashhad Iran
| | - Mir Hadi Jazayeri
- Immunology Research Center and Department of Immunology, School of Medicine Iran University of Medical Sciences Tehran Iran
| | - Mohammadreza Nasiri
- Recombinant Proteins Research Group The Research Institute of Biotechnology, Ferdowsi University of Mashhad Mashhad Iran
| | - Amir Avan
- Metabolic Syndrome Research Center Mashhad University of Medical Sciences Mashhad Iran
- Cancer Research Center Mashhad University of Medical Sciences Mashhad Iran
- Department of Modern Sciences and Technologies, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
- Surgical Oncology Research Center Mashhad University of Medical Sciences Mashhad Iran
| | - Majid Khazaei
- Department of Physiology, Faculty of Medicine Mashhad University of Medical Sciences Mashhad Iran
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MiR-29b affects the secretion of PROG and promotes the proliferation of bovine corpus luteum cells. PLoS One 2018; 13:e0195562. [PMID: 29617446 PMCID: PMC5884578 DOI: 10.1371/journal.pone.0195562] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 03/23/2018] [Indexed: 12/31/2022] Open
Abstract
The regulatory role of miRNAs has been explored in ovarian cells, and their effects on gonadal development, apoptosis, ovulation, steroid production and corpus luteum (CL) development have been revealed. In this study, we analyzed the expression of miR-29b at different stages of bovine CL development and predicted the target genes of miR-29b. We confirmed that miR-29b reduces the expression of the oxytocin receptor (OXTR), affects progesterone (PROG) secretion and regulates the function of the CL. RT-PCR showed that the expression of miR-29b was significantly higher in functional CL phases than in the regressed CL phase. Immunohistochemistry showed that OXTR was expressed in both large and small CL cells and was mainly located in the cell membrane and cytoplasm of these cells. We analyzed the expression levels of OXTR and found that transfection with a miR-29b mimic decreased OXTR expression, but transfection with the inhibitor had a limited effect on the expression of the OXTR protein. At the same time, the secretion of PROG was significantly increased in the miR-29b mimic-transfected group. We also analyzed the effect of miR-29b on the apoptosis of CL cells. Finally, we found that miR-29b could promote the proliferation of bovine CL cells. In conclusion, we found that miR-29b reduces the expression of OXTR and can promote PROG secretion and the proliferation of CL cells via OXTR.
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Yin H, Que R, Liu C, Ji W, Sun B, Lin X, Zhang Q, Zhao X, Peng Z, Zhang X, Qian H, Chen L, Yao Y, Su C. Survivin-targeted drug screening platform identifies a matrine derivative WM-127 as a potential therapeutics against hepatocellular carcinoma. Cancer Lett 2018; 425:54-64. [PMID: 29608986 DOI: 10.1016/j.canlet.2018.03.044] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/26/2018] [Accepted: 03/27/2018] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death which needs novel drugs to improve patient outcome. Survivin overexpresses in HCC and contributes to HCC malignant progression. In this study, we established a Survivin-targeted drug screening platform, a cell model HepG2-Sur5P-EGFP-Sur3U stably transfected with lentivirus carrying an EGFP expression cassette, in which the EGFP expression was regulated by the upstream Survivin promoter and downstream Survivin 3'-UTR. By using this platform, we screened and easily identified one of matrine derivatives, WM-127, from hundreds of matrine derivatives. WM-127 was demonstrated to be a strong Survivin inhibitor that inhibited cell proliferation, induced cell cycle arrest and apoptosis of HCC cells, and suppressed the growth of HCC xenografted tumors in nude mice, suggesting that WM-127 might be a promising drug for HCC treatment. WM-127 exhibited less cytotoxicity in normal cells. Mechanistic studies showed that WM-127 suppressed the activity of Survivin/β-catenin pathway and the expression of Bax to induce cell cycle arrest and apoptosis. Taken together, we constructed an economical, practical, efficient and convenient cell platform for screening the Survivin-targeted drugs from the enormous diversity of chemicals or factors, which would be a potential tool for antitumor drug research and development.
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Affiliation(s)
- Haisen Yin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China; Department of Gastroenterology, Jingzhou Central Hospital & Clinical Medical College, Yangtze University, Jingzhou, 434023, Hubei Province, China
| | - Risheng Que
- Department of Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China
| | - Chunying Liu
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Weidan Ji
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Bin Sun
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Xuejing Lin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Qin Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Xinying Zhao
- Department of Gastroenterology, Jingzhou Central Hospital & Clinical Medical College, Yangtze University, Jingzhou, 434023, Hubei Province, China
| | - Zhangxiao Peng
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Xiaofeng Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Haihua Qian
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Lei Chen
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China
| | - Yonggang Yao
- Department of Gastroenterology, Jingzhou Central Hospital & Clinical Medical College, Yangtze University, Jingzhou, 434023, Hubei Province, China
| | - Changqing Su
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, 200438, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, 221002, Jiangsu, China.
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Survivin-Based Treatment Strategies for Squamous Cell Carcinoma. Int J Mol Sci 2018; 19:ijms19040971. [PMID: 29587347 PMCID: PMC5979467 DOI: 10.3390/ijms19040971] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/20/2018] [Accepted: 03/21/2018] [Indexed: 02/07/2023] Open
Abstract
Survivin, an anti-apoptotic molecule abundantly expressed in most human neoplasms, has been reported to contribute to cancer initiation and drug resistance in a wide variety of human tumors. Efficient downregulation of survivin can sensitize tumor cells to various therapeutic interventions, generating considerable efforts in its validation as a new target in cancer therapy. This review thoroughly analyzes up-to-date information on the potential of survivin as a therapeutic target for new anticancer treatments. The literature dealing with the therapeutic targeting of survivin will be reviewed, discussing specifically squamous cell carcinomas (SCCs), and with emphasis on the last clinical trials. This review gives insight into the recent developments undertaken in validating various treatment strategies that target survivin in SCCs and analyze the translational possibility, identifying those strategies that seem to be the closest to being incorporated into clinical practice. The most recent developments, such as dominant-negative survivin mutants, RNA interference, anti-sense oligonucleotides, small-molecule inhibitors, and peptide-based immunotherapy, seem to be helpful for effectively downregulating survivin expression and reducing tumor growth potential, increasing the apoptotic rate, and sensitizing tumor cells to chemo- and radiotherapy. However, selective and efficient targeting of survivin in clinical trials still poses a major challenge.
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Chen JF, Luo X, Xiang LS, Li HT, Zha L, Li N, He JM, Xie GF, Xie X, Liang HJ. EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signaling. Oncotarget 2018; 7:41540-41558. [PMID: 27172794 PMCID: PMC5173077 DOI: 10.18632/oncotarget.9236] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 04/24/2016] [Indexed: 02/05/2023] Open
Abstract
Because colorectal cancer (CRC) stem-like cells (CCS-like cells) contribute to poor patient prognosis, these cells are a potential target for CRC therapy. However, the mechanism underlying the maintenance of CCS-like cell properties remains unclear. Here, we found that patients with advanced stage CRC expressed high levels of polycomb group protein enhancer of zeste homologue 2 (EZH2). High expression of EZH2 in tumor tissues correlated with poor patient prognosis. Conversely, silencing EZH2 reduced CRC cell proliferation. Surprisingly, EZH2 was more highly expressed in the CCS-like cell subpopulation than in the non-CCS-like cell subpopulation. EZH2 knockdown significantly reduced the CD133+/CD44+ subpopulation, suppressed mammosphere formation, and decreased the expression of self-renewal-related genes and strongly impaired tumor-initiating capacity in a re-implantation mouse model. Gene expression data from 433 human CRC specimens from TCGA database and in vitro results revealed that EZH2 helped maintain CCS-like cell properties by activating the Wnt/β-catenin pathway. We further revealed that p21cip1–mediated arrest of the cell cycle at G1/S phase is required for EZH2 activation of the Wnt/β-catenin pathway. Moreover, the specific EZH2 inhibitor EPZ-6438, a clinical trial drug, prevented CRC progression. Collectively, these findings revealed EZH2 maintaining CCS-like cell characteristics by arresting the cell cycle at the G1/S phase. These results indicate a new approach to CRC therapy.
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Affiliation(s)
- Jian-Fang Chen
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xi Luo
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Li-Sha Xiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan, China
| | - Hong-Tao Li
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Lin Zha
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ni Li
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Jian-Ming He
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Gan-Feng Xie
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiong Xie
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Hou-Jie Liang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
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Yin L, Gao Y, Zhang X, Wang J, Ding D, Zhang Y, Zhang J, Chen H. Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/β-catenin signaling. Oncotarget 2018; 7:42126-42138. [PMID: 27363012 PMCID: PMC5173121 DOI: 10.18632/oncotarget.9704] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/16/2016] [Indexed: 01/22/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is one of the most difficult breast cancers to treat because there is no targeted treatment, and conventional cytotoxic chemotherapy followed by adjuvant radiation therapy is the standard of care for patients with TNBC. We herein reported that ionizing radiation (IR) induced Wnt3a, LRP6 and β-catenin expression and consequently activated Wnt/β-catenin signaling in TNBC MDA-MB-231, MDA-MB-468 and Hs578T cells. Moreover, depletion of β-catenin by shRNA sensitized TNBC cells to IR, whereas treatment of Wnt3a protein or overexpression of β-catenin resulted in radioresistance of TNBC cells. Niclosamide, a potent inhibitor of Wnt/β-catenin signaling, not only inhibited constitutive Wnt/β-catenin signaling, but also blocked IR-induced Wnt/β-catenin signaling in TNBC cells. In addition, niclosamide sensitized TNBC cells to IR, prevented Wnt3a-induced radioresistance, and overcame β-catenin-induced radioresistance in TNBC cells. Importantly, animals treated with the combination of niclosamide and γ-ray local tumor irradiation had significant inhibition of MDA-MB-231 tumor growth compared with treated with local tumor irradiation alone. These findings indicate that Wnt/β-catenin signaling pathway plays an important role in the development of radioresistance of TNBC cells, and that niclosamide had significant radiosensitizing effects by inhibiting Wnt/β-catenin signaling in TNBC cells. Our study also provides rationale for further preclinical and clinical evaluation of niclosamide in TNBC management.
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Affiliation(s)
- Lina Yin
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Yun Gao
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Xuxia Zhang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Jing Wang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Defang Ding
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Yaping Zhang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Junxiang Zhang
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
| | - Honghong Chen
- Department of Radiation Biology, Institute of Radiation Medicine, Fudan University, Shanghai, China
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Li Y, Lu W, Saini SK, Moukha-Chafiq O, Pathak V, Ananthan S. Identification of quinazoline compounds as novel potent inhibitors of Wnt/β-catenin signaling in colorectal cancer cells. Oncotarget 2017; 7:11263-70. [PMID: 26820295 PMCID: PMC4905471 DOI: 10.18632/oncotarget.7019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 01/13/2016] [Indexed: 01/27/2023] Open
Abstract
The Wnt/β-catenin signaling pathway is critical for the initiation and progression of most colon cancers, and has emerged as one of the most promising targets for colorectal cancer chemoprevention and treatment. In this study, we have discovered a structurally related series of quinazolines as potent inhibitors of Wnt/β-catenin signaling in colorectal cancer cells harboring mutations in CTNNB1 or APC. We showed that the quinazoline leads suppressed Wnt/β-catenin signaling without altering the level of β-catenin protein in colorectal cancer cells, suggesting that they act on the downstream elements of the pathway. Moreover, the quinazoline leads displayed potent anticancer activities with IC50 values between 4.9 and 17.4 μM in colorectal cancer cells. Importantly, we also found that a structurally related quinazoline lacking inhibitory effect on Wnt/β-catenin signaling was unable to suppress colorectal cancer cell proliferation. Together, these results suggest that the quinazoline lead compounds identified in this study have therapeutic potential for the prevention and treatment of colorectal cancer.
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Affiliation(s)
- Yonghe Li
- Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, United States of America
| | - Wenyan Lu
- Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, United States of America
| | - Surendra K Saini
- Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, United States of America
| | - Omar Moukha-Chafiq
- Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, United States of America
| | - Vibha Pathak
- Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, United States of America
| | - Subramaniam Ananthan
- Drug Discovery Division, Southern Research Institute, Birmingham, AL 35205, United States of America
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Oh S, Kim H, Nam K, Shin I. Silencing of Glut1 induces chemoresistance via modulation of Akt/GSK-3β/β-catenin/survivin signaling pathway in breast cancer cells. Arch Biochem Biophys 2017; 636:110-122. [DOI: 10.1016/j.abb.2017.08.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 07/24/2017] [Accepted: 08/09/2017] [Indexed: 12/29/2022]
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