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Zhang S, Lv J, Cheng X, Chen K, Wei Q, Gong X, Xiao W, Huang X, Du E, Xiu L, Ji W, Li JL. Provoking Lysosome Disruption via In Situ Engineered Double-Network Assemblies for Targeted Cancer Cell Death. ACS NANO 2025; 19:12208-12221. [PMID: 40114430 DOI: 10.1021/acsnano.5c00268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Increasing evidence has demonstrated the critical role of lysosomes in tumor progression, as well as their involvement in drug resistance during cancer treatment. However, the exploitation of lysosome-targeting agents to inhibit malignant cell growth is still in high demand. Herein, we report an alkaline phosphatase (ALP)-responsive peptide-based precursor (C1) that selectively induced lysosome dysfunction in uveal melanoma cells via noncontact light manipulation. We demonstrated that C1 was dephosphorylated upon close contact with ALP-upregulated tumor cells, endocytosed, and accumulated in lysosomes. Further light irradiation facilitated the generation of two self-sorting components that self-assembled to form nanofibrils and nanorods, respectively. Mesoscale interactions between these two nanostructures triggered the formation of robust double-network assemblies within lysosomes, resulting in lysosomal membrane permeabilization and tumor cell death. By strategically utilizing ALP activity, light responsiveness, and lysosomal acidity in the design of a self-assembling precursor, we have developed double-network assemblies capable of selectively disrupting lysosomal membrane integrity and effectively inhibiting tumor cells. These findings provide valuable insights for the advancement of lysosome-targeting therapeutic agents.
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Affiliation(s)
- Shijin Zhang
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Jiarong Lv
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Xinglan Cheng
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Ke Chen
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Qinchuan Wei
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Xuewen Gong
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Wei Xiao
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Xinyuan Huang
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Enming Du
- Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan University of School of Medicine, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Linyun Xiu
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
| | - Wei Ji
- Key Laboratory of Biorheological Science and Technology Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Ji-Liang Li
- National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China
- Wenzhou Institute, University of Chinese Academy of Sciences, 1 Jinlian Road, Wenzhou 325001, China
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Li L, Fan Z, Liu M, Dong H, Li J, Li Y, Song Z, Liu Y, Zhang Z, Gu X, Zhang T. USP1 promotes pancreatic cancer progression and autophagy by deubiquitinating ATG14. J Biol Chem 2025; 301:108190. [PMID: 39814232 PMCID: PMC11871461 DOI: 10.1016/j.jbc.2025.108190] [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: 10/28/2024] [Revised: 12/24/2024] [Accepted: 01/08/2025] [Indexed: 01/18/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis, high mortality, and limited therapeutic strategy. Autophagy is hyperactivated in PDAC, and targeting autophagy is emerging as a promising therapeutic strategy. The dysfunction of deubiquitinase ubiquitin-specific peptidase 1 (USP1) results in tumorigenesis and chemotherapy resistance. However, little is known about how USP1 regulates autophagy and its mechanism in tumor progression and drug sensitivity in PDAC. In this study, we found USP1 elevated in pancreatic cancer and USP1 expression inversely correlated with overall survival. USP1 depletion inhibited cell proliferation, epithelial-mesenchymal transition, and migration in PDAC cells. Interestingly, USP1 knockdown or inhibition reduced autophagy initiation and autophagy flux. By screening of interacting protein using coimmunoprecipitation, we identified that USP1 interacted with ATG14 (autophagy-related gene 14) protein, acting as a core component in autophagy initiation. Furthermore, USP1 overexpression deubiquitinated and enhanced ATG14 protein stability by reduced binding ubiquitin levels, whereas USP1 inhibition promoted its proteasome-dependent degradation. Notably, USP1 depletion or a novel USP1 inhibitor I-138 dramatically delayed tumor growth in xenograft model. USP1 inhibitor synergistically enhanced the anticancer efficiency of cisplatin in PDAC cells. Collectively, our study identifies USP1 as the first deubiquitinase in the modulation of ATG14 deubiquitination and unveils a regulatory role for USP1 in autophagy and PDAC progression. Targeting USP1 using a selective inhibitor I-138 may provide an effective strategy for chemotherapy treatment and combating drug resistance in autophagy-activated pancreatic cancer.
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Affiliation(s)
- Leilei Li
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Zhili Fan
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Mengfei Liu
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Hao Dong
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jing Li
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yu Li
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Zan Song
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ying Liu
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Zhicheng Zhang
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xinyu Gu
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Tao Zhang
- Institute of Immunopharmaceutical Sciences, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin, Guangxi, China.
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Soon JW, Manca MA, Laskowska A, Starkova J, Rohlenova K, Rohlena J. Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167451. [PMID: 39111633 DOI: 10.1016/j.bbadis.2024.167451] [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: 05/10/2024] [Revised: 07/19/2024] [Accepted: 07/31/2024] [Indexed: 08/11/2024]
Abstract
Aspartate is a proteinogenic non-essential amino acid with several essential functions in proliferating cells. It is mostly produced in a cell autonomous manner from oxalacetate via glutamate oxalacetate transaminases 1 or 2 (GOT1 or GOT2), but in some cases it can also be salvaged from the microenvironment via transporters such as SLC1A3 or by macropinocytosis. In this review we provide an overview of biosynthetic pathways that produce aspartate endogenously during proliferation. We discuss conditions that favor aspartate uptake as well as possible sources of exogenous aspartate in the microenvironment of tumors and bone marrow, where most available data have been generated. We highlight metabolic fates of aspartate, its various functions, and possible approaches to target aspartate metabolism for cancer therapy.
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Affiliation(s)
- Julian Wong Soon
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic
| | - Maria Antonietta Manca
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic
| | - Agnieszka Laskowska
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic
| | - Julia Starkova
- CLIP (Childhood Leukaemia Investigation Prague), Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Katerina Rohlenova
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic.
| | - Jakub Rohlena
- Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Prague-West, Czech Republic.
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Deng S, Liu Y, Liu X, Yu J, Chen Y, Huo J. Inhibition of colorectal cancer aggressiveness by Oleanolic acid through Nur77 degradation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156192. [PMID: 39520953 DOI: 10.1016/j.phymed.2024.156192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Colorectal cancer (CRC) is the second primary malignancy in China with tough treatment challenge. Although Oleanolic acid (OA) protects against various cancers, its mechanisms in CRC are not well defined. Our previously study showed that Nur77 has CRC promoting effect. Thus, we investigated the roles of OA as Nur77 ligand and the regulatory effects on Nur77 degradation in CRC progression. METHODS The proliferative and metastatic phenotypes of OA was examined by CCK-8, EdU, organoid culture, would healing and transwell assays, respectively. Epithelial-mesenchymal transition (EMT) properties were assessed by Western blotting (WB). The interaction between OA and Nur77 was monitored by molecular docking and Molecular Dynamics stimulation (MD). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were employed to screen the downstream regulatory pathways. The half-time and proteasome degradation of Nur77 were treated with cycloheximide (CHX) and MG132. Co-immunoprecipitation (Co-IP) and ubiquitination assays were employed to detect direct association between Nur77 and PPARγ. Rescued experiments were performed by Nur77 agonist Cytosporone B (Csn-B) treatment. The findings were verified in xenograft and in situ models. RESULTS For the first time, we found the effect of OA on ubiquitination degradation. OA inhibited CRC cell survival and EMT phenotypes by suppressing Nur77. Mechanistically, OA directly bind to Nur77 and facilitated the ubiquitin degradation of Nur77. During this process, PPARγ acted as the ubiquitination activator via interacting with Nur77. Rescued experiments revealed that OA-induced inhibition was recovered by replenishing Nur77. In both subcutaneous and orthotopic CRC models, OA exhibited significant anti-tumor effect together with Nur77 inhibition. CONCLUSION We revealed a new regulatory effect of OA in CRC tumorigenesis via PPARγ-mediated Nur77 ubiquitin degradation.
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Affiliation(s)
- Shan Deng
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
| | - Yuping Liu
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Xiyu Liu
- Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, People's Republic of China
| | - Jialin Yu
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Yan Chen
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China; Research Center for Multicomponent of Traditional Chinese Medicine and Microecology, Jiangsu Provincial Academy of Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu, 210028, People's Republic of China.
| | - Jiege Huo
- The Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China; Department of Oncology, Jiangsu Province Academy of Traditional Chinese Medicine, 100 Shizi Road, Nanjing, Jiangsu, 210028, People's Republic of China.
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5
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Sánchez-Castillo A, Savelkouls KG, Baldini A, Hounjet J, Sonveaux P, Verstraete P, De Keersmaecker K, Dewaele B, Björkblom B, Melin B, Wu WY, Sjöberg RL, Rouschop KMA, Broen MPG, Vooijs M, Kampen KR. Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas. Oncogenesis 2024; 13:39. [PMID: 39537592 PMCID: PMC11561346 DOI: 10.1038/s41389-024-00540-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024] Open
Abstract
The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPHV116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/glyhigh glioblastoma models. Interestingly, ser/glyhigh glioblastomas, including PSPHamp and PSPHV116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/glyhigh glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/glyhigh cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/glyhigh glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.
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Affiliation(s)
- Anaís Sánchez-Castillo
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Kim G Savelkouls
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Alessandra Baldini
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Judith Hounjet
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Pierre Sonveaux
- Pole of Pharmacology, Institut de Recherche Experimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
- WEL Research Institute, WELBIO Department, Wavre, Belgium
| | - Paulien Verstraete
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Kim De Keersmaecker
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium
| | - Barbara Dewaele
- Center for Human Genetics, Laboratory for Genetics of Malignant Disorders, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | | | - Beatrice Melin
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Wendy Y Wu
- Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden
| | - Rickard L Sjöberg
- Department of Clinical Science, Neurosciences, Umeå University, Umeå, Sweden
| | - Kasper M A Rouschop
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Martijn P G Broen
- Department of Neurology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Marc Vooijs
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands
| | - Kim R Kampen
- Department of Radiation Oncology (MAASTRO), Maastricht University Medical Center, GROW School for Oncology and Reproduction, Maastricht, The Netherlands.
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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Wu H, Fu M, Wu M, Cao Z, Zhang Q, Liu Z. Emerging mechanisms and promising approaches in pancreatic cancer metabolism. Cell Death Dis 2024; 15:553. [PMID: 39090116 PMCID: PMC11294586 DOI: 10.1038/s41419-024-06930-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/04/2024]
Abstract
Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.
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Affiliation(s)
- Hao Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Mengdi Fu
- Department of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Mengwei Wu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Zhen Cao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qiyao Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Ziwen Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Lu X, Yao Y, Ma Y, Zhang X, Peng H, Pei Y, Lu Y, Wang L. Low expression of PINK1 and PARK2 predicts poor prognosis in patients with esophageal squamous cell carcinoma. World J Surg Oncol 2023; 21:321. [PMID: 37833780 PMCID: PMC10571472 DOI: 10.1186/s12957-023-03206-3] [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: 07/12/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND The Parkinson's disease (PD) gene family expression is strongly linked to tumor development and progression; PINK1 and PARK2 are essential members of the PD gene family. However, the relationship between PINK1 and PARK2 and esophageal squamous cell carcinoma (ESCC) remains unknown. This research aims to clarify the prognostic value of PINK1 and PARK2 in ESCC. METHODS PINK1 and PARK2 protein levels in 232 ESCC specimens, and 125 matched adjacent normal tissues were detected by immunohistochemistry. The relationship between PINK1 and PARK2 protein expression and clinicopathological features were analyzed. Kaplan-Meier survival analysis was performed to estimate the prognostic value of the PINK1 and PARK2 proteins in patients. Cox univariate and multivariate analyses were used to assess the risk factors affecting the OS for patients with ESCC. RESULTS PINK1 and PARK2 had low expression in ESCC. Patients with low PINK1 had worse differentiation and advanced T and TNM stages. Lower PARK2 expression was linked to lymph node metastases and an advanced TNM stage. Furthermore, reduced PINK1 and PARK2 levels were associated with a poor prognosis for ESCC. Cox univariate and multivariate analyses revealed that PINK1, PARK2, and tumor size were closely associated with the prognosis of patients with ESCC, and PARK2 was an independent risk factor for patients with ESCC. Finally, the PINK1 and PARK2 proteins were closely related and shared the same signal pathway. CONCLUSIONS PINK1 and PARK2 could work as tumor suppressors in ESCC and are likely to become new treatment targets for ESCC.
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Affiliation(s)
- Xiangyun Lu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, the First Affiliated Hospital/Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yongkun Yao
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, the First Affiliated Hospital/Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yandi Ma
- Department of Pathology, Nanyang Central Hospital, Nanyang, Henan, China
| | - Xudong Zhang
- Department of Pathology, the First Clinical Medical College of Weifang Medical University, Weifang People's Hospital, Weifang, Shangdong, China
| | - Hao Peng
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, the First Affiliated Hospital/Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yuhui Pei
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, the First Affiliated Hospital/Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Yulin Lu
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, the First Affiliated Hospital/Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Lianghai Wang
- Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, the First Affiliated Hospital/Shihezi University School of Medicine, Shihezi, Xinjiang, China.
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8
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Gutierrez-Ruiz OL, Johnson KM, Krueger EW, Nooren RE, Cruz-Reyes N, Heppelmann CJ, Hogenson TL, Fernandez-Zapico ME, McNiven MA, Razidlo GL. Ectopic expression of DOCK8 regulates lysosome-mediated pancreatic tumor cell invasion. Cell Rep 2023; 42:113042. [PMID: 37651233 PMCID: PMC10591794 DOI: 10.1016/j.celrep.2023.113042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 06/22/2023] [Accepted: 08/11/2023] [Indexed: 09/02/2023] Open
Abstract
Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor growth and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 8 (DOCK8) on lysosomes. Surprisingly, DOCK8 is aberrantly expressed in a subset of PDAC, where it promotes cell invasion in vitro and in vivo. DOCK8 associates with lysosomes and regulates lysosomal morphology and motility, with loss of DOCK8 leading to increased lysosome size. DOCK8 promotes actin polymerization at the surface of lysosomes while also increasing the proteolytic activity of the lysosomal protease cathepsin B. Critically, depletion of DOCK8 significantly reduces cathepsin-dependent extracellular matrix degradation and impairs the invasive capacity of PDAC cells. These findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation and invasion in pancreatic cancer cells.
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Affiliation(s)
- Omar L Gutierrez-Ruiz
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Katherine M Johnson
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Eugene W Krueger
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Roseanne E Nooren
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | - Nicole Cruz-Reyes
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Tara L Hogenson
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Martin E Fernandez-Zapico
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Mark A McNiven
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
| | - Gina L Razidlo
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
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9
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Zhou Z, Bonds MM, Edil BH, Houchen CW, Liu Z, Li M. Lysosomes Promote Cancer Metastasis via Exosome in PTEN-Deficient Tumors. Gastroenterology 2023; 164:329-331. [PMID: 36608713 DOI: 10.1053/j.gastro.2022.12.034] [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: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 01/09/2023]
Affiliation(s)
- Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Morgan M Bonds
- Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Barish H Edil
- Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Courtney W Houchen
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
| | - Min Li
- Department of Medicine and, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
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10
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Akter F, Bonini S, Ponnaiyan S, Kögler-Mohrbacher B, Bleibaum F, Damme M, Renard BY, Winter D. Multi-Cell Line Analysis of Lysosomal Proteomes Reveals Unique Features and Novel Lysosomal Proteins. Mol Cell Proteomics 2023; 22:100509. [PMID: 36791992 PMCID: PMC10025164 DOI: 10.1016/j.mcpro.2023.100509] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 02/01/2023] [Accepted: 02/06/2023] [Indexed: 02/15/2023] Open
Abstract
Lysosomes, the main degradative organelles of mammalian cells, play a key role in the regulation of metabolism. It is becoming more and more apparent that they are highly active, diverse, and involved in a large variety of processes. The essential role of lysosomes is exemplified by the detrimental consequences of their malfunction, which can result in lysosomal storage disorders, neurodegenerative diseases, and cancer. Using lysosome enrichment and mass spectrometry, we investigated the lysosomal proteomes of HEK293, HeLa, HuH-7, SH-SY5Y, MEF, and NIH3T3 cells. We provide evidence on a large scale for cell type-specific differences of lysosomes, showing that levels of distinct lysosomal proteins are highly variable within one cell type, while expression of others is highly conserved across several cell lines. Using differentially stable isotope-labeled cells and bimodal distribution analysis, we furthermore identify a high confidence population of lysosomal proteins for each cell line. Multi-cell line correlation of these data reveals potential novel lysosomal proteins, and we confirm lysosomal localization for six candidates. All data are available via ProteomeXchange with identifier PXD020600.
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Affiliation(s)
- Fatema Akter
- Institute for Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Bonn, Germany; Department of Pharmacology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh
| | - Sara Bonini
- Institute for Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Bonn, Germany
| | - Srigayatri Ponnaiyan
- Institute for Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Bonn, Germany
| | | | | | - Markus Damme
- Institute for Biochemistry, University of Kiel, Kiel, Germany
| | | | - Dominic Winter
- Institute for Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Bonn, Germany.
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11
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Tan J, Zhou S, Zhang W, Yang B, Zhong G, Huang J, Hu H, Han F, Luo M. Long noncoding RNA OVAAL enhances nucleotide synthesis through pyruvate carboxylase to promote 5-fluorouracil resistance in gastric cancer. Cancer Sci 2022; 113:3055-3070. [PMID: 35657686 PMCID: PMC9459305 DOI: 10.1111/cas.15453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 05/23/2022] [Accepted: 05/29/2022] [Indexed: 12/09/2022] Open
Abstract
5-Fluorouracil (5-FU) is widely used in gastric cancer treatment, yet 5-FU resistance remains an important clinical challenge. We established a model based on five long noncoding RNAs (lncRNA) to effectively assess the prognosis of gastric cancer patients; among them, lncRNA OVAAL was markedly upregulated in gastric cancer and associated with poor prognosis and 5-FU resistance. In vitro and in vivo assays confirmed that OVAAL promoted proliferation and 5-FU resistance of gastric cancer cells. Mechanistically, OVAAL bound with pyruvate carboxylase (PC) and stabilized PC from HSC70/CHIP-mediated ubiquitination and degradation. OVAAL knockdown reduced intracellular levels of oxaloacetate and aspartate, and the subsequent pyrimidine synthesis, which could be rescued by PC overexpression. Moreover, OVAAL knockdown increased sensitivity to 5-FU treatment, which could be reversed by PC overexpression or repletion of oxaloacetate, aspartate, or uridine. OVAAL overexpression enhanced pyrimidine synthesis to promote proliferation and 5-FU resistance of gastric cancer cells, which could be abolished by PC knockdown. Thus, OVAAL promoted gastric cancer cell proliferation and induced 5-FU resistance by enhancing pyrimidine biosynthesis to antagonize 5-FU induced thymidylate synthase dysfunction. Targeting OVAAL-mediated nucleotide metabolic reprograming would be a promising strategy to overcome chemoresistance in gastric cancer.
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Affiliation(s)
- Jia‐nan Tan
- Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Sheng‐ning Zhou
- Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Wei Zhang
- Department of Oncology, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Bin Yang
- Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Guang‐yu Zhong
- Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Jing Huang
- Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Hai Hu
- Department of Oncology, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Fang‐hai Han
- Department of Gastrointestinal Surgery, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Man‐Li Luo
- Medical Research Center, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong‐Hong Kong Joint Laboratory for RNA Medicine, Sun Yat‐Sen Memorial HospitalSun Yat‐Sen UniversityGuangzhouChina
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12
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Application of meso-CF 3-Fluorophore BODIPY with Phenyl and Pyrazolyl Substituents for Lifetime Visualization of Lysosomes. Molecules 2022; 27:molecules27155018. [PMID: 35956971 PMCID: PMC9370186 DOI: 10.3390/molecules27155018] [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: 07/06/2022] [Revised: 07/26/2022] [Accepted: 08/04/2022] [Indexed: 11/16/2022] Open
Abstract
A bright far-red emitting unsymmetrical meso-CF3-BODIPY fluorescent dye with phenyl and pyrazolyl substituents was synthesized by condensation of trifluoropyrrolylethanol with pyrazolyl-pyrrole, with subsequent oxidation and complexation of the formed dipyrromethane. This BODIPY dye exhibits optical absorption at λab ≈ 610-620 nm and emission at λem ≈ 640-650 nm. The BODIPY was studied on Ehrlich carcinoma cells as a lysosome-specific fluorescent dye that allows intravital staining of cell structures with subsequent real-time monitoring of changes occurring in the cells. It was also shown that the rate of uptake by cells, the rate of intracellular transport into lysosomes, and the rate of saturation of cells with the dye depend on its concentration in the culture medium. A concentration of 5 μM was chosen as the most suitable BODIPY concentration for fluorescent staining of living cell lysosomes, while a concentration of 100 μM was found to be toxic to Ehrlich carcinoma cells.
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13
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Nishimoto A. Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment. World J Gastroenterol 2022; 28:3637-3643. [PMID: 36161054 PMCID: PMC9372808 DOI: 10.3748/wjg.v28.i28.3637] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/06/2022] [Accepted: 06/30/2022] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is highly aggressive and lethal. Due to the lack of effective methods for detecting the disease at an early stage, pancreatic cancer is frequently diagnosed late. Gemcitabine has been the standard chemotherapy drug for patients with pancreatic cancer for over 20 years, but its anti-tumor effect is limited. Therefore, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) as well as combination therapies using gemcitabine and conventional agents, such as cisplatin and capecitabine, has also been administered; however, these have not resulted in complete remission. Therefore, there is a need to develop novel and effective therapies for pancreatic cancer. Recently, some studies have reported that combinations of gemcitabine and targeted drugs have had significant anti-tumor effects on pancreatic cancer cells. As gemcitabine induced DNA damage response, the proteins related to DNA damage response can be suitable additional targets for novel gemcitabine-based combination therapy. Furthermore, KRAS/ RAF/MEK/ERK signaling triggered by oncogenic mutated KRAS and autophagy are frequently activated in pancreatic cancer. Therefore, these characteristics of pancreatic cancer are potential targets for developing effective novel therapies. In this minireview, combinations of gemcitabine and targeted drugs to these characteristics, combinations of targeted drugs, combinations of natural products and anti-cancer agents, including gemcitabine, and combinations among natural products are discussed.
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Affiliation(s)
- Arata Nishimoto
- Division of Basic Pharmaceutical Science, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda City 756-0884, Yamaguchi, Japan
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14
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Hernandez GA, Perera RM. Autophagy in cancer cell remodeling and quality control. Mol Cell 2022; 82:1514-1527. [PMID: 35452618 PMCID: PMC9119670 DOI: 10.1016/j.molcel.2022.03.023] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 03/01/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022]
Abstract
As one of the two highly conserved cellular degradation systems, autophagy plays a critical role in regulation of protein, lipid, and organelle quality control and cellular homeostasis. This evolutionarily conserved pathway singles out intracellular substrates for elimination via encapsulation within a double-membrane vesicle and delivery to the lysosome for degradation. Multiple cancers disrupt normal regulation of autophagy and hijack its degradative ability to remodel their proteome, reprogram their metabolism, and adapt to environmental challenges, making the autophagy-lysosome system a prime target for anti-cancer interventions. Here, we discuss the roles of autophagy in tumor progression, including cancer-specific mechanisms of autophagy regulation and the contribution of tumor and host autophagy in metabolic regulation, immune evasion, and malignancy. We further discuss emerging proteomics-based approaches for systematic profiling of autophagosome-lysosome composition and contents. Together, these approaches are uncovering new features and functions of autophagy, leading to more effective strategies for targeting this pathway in cancer.
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Affiliation(s)
- Grace A Hernandez
- Department of Anatomy, Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Rushika M Perera
- Department of Anatomy, Department of Pathology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
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15
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Nanoprodrug ratiometrically integrating autophagy inhibitor and genotoxic agent for treatment of triple-negative breast cancer. Biomaterials 2022; 283:121458. [DOI: 10.1016/j.biomaterials.2022.121458] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/25/2022] [Accepted: 03/03/2022] [Indexed: 12/12/2022]
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16
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Redding A, Aplin AE, Grabocka E. RAS-mediated tumor stress adaptation and the targeting opportunities it presents. Dis Model Mech 2022; 15:dmm049280. [PMID: 35147163 PMCID: PMC8844456 DOI: 10.1242/dmm.049280] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cellular stress is known to function in synergistic cooperation with oncogenic mutations during tumorigenesis to drive cancer progression. Oncogenic RAS is a strong inducer of a variety of pro-tumorigenic cellular stresses, and also enhances the ability of cells to tolerate these stresses through multiple mechanisms. Many of these oncogenic, RAS-driven, stress-adaptive mechanisms have also been implicated in tolerance and resistance to chemotherapy and to therapies that target the RAS pathway. Understanding how oncogenic RAS shapes cellular stress adaptation and how this functions in drug resistance is of vital importance for identifying new therapeutic targets and therapeutic combinations to treat RAS-driven cancers.
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Affiliation(s)
| | | | - Elda Grabocka
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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17
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Abt ER, Le TM, Dann AM, Capri JR, Poddar S, Lok V, Li L, Liang K, Creech AL, Rashid K, Kim W, Wu N, Cui J, Cho A, Lee HR, Rosser EW, Link JM, Czernin J, Wu TT, Damoiseaux R, Dawson DW, Donahue TR, Radu CG. Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells. Cell Rep 2022; 38:110236. [PMID: 35021095 PMCID: PMC8893345 DOI: 10.1016/j.celrep.2021.110236] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/22/2021] [Accepted: 12/16/2021] [Indexed: 01/19/2023] Open
Abstract
We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.
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Affiliation(s)
- Evan R Abt
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Thuc M Le
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Amanda M Dann
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Joseph R Capri
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Soumya Poddar
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Vincent Lok
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Luyi Li
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Keke Liang
- Department of General Surgery/Pancreatic and Thyroid Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Amanda L Creech
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Khalid Rashid
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Woosuk Kim
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Nanping Wu
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA
| | - Jing Cui
- Department of Pancreatic Surgery, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China
| | - Arthur Cho
- Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Hailey Rose Lee
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Ethan W Rosser
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Jason M Link
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
| | - Johannes Czernin
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA
| | - Ting-Ting Wu
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Robert Damoiseaux
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA, USA; Department of Bioengineering, Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA
| | - David W Dawson
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Timothy R Donahue
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA; Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
| | - Caius G Radu
- Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Theranostics Division, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
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18
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Klomp JE, Lee YS, Goodwin CM, Papke B, Klomp JA, Waters AM, Stalnecker CA, DeLiberty JM, Drizyte-Miller K, Yang R, Diehl JN, Yin HH, Pierobon M, Baldelli E, Ryan MB, Li S, Peterson J, Smith AR, Neal JT, McCormick AK, Kuo CJ, Counter CM, Petricoin EF, Cox AD, Bryant KL, Der CJ. CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment. Cell Rep 2021; 37:110060. [PMID: 34852220 PMCID: PMC8665414 DOI: 10.1016/j.celrep.2021.110060] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 09/09/2021] [Accepted: 11/03/2021] [Indexed: 12/17/2022] Open
Abstract
We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.
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Affiliation(s)
- Jennifer E Klomp
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ye S Lee
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Craig M Goodwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Björn Papke
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jeff A Klomp
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Andrew M Waters
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Clint A Stalnecker
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jonathan M DeLiberty
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kristina Drizyte-Miller
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Runying Yang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - J Nathaniel Diehl
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Hongwei H Yin
- Departments of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Mariaelena Pierobon
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Elisa Baldelli
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Meagan B Ryan
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Siqi Li
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC
| | - Jackson Peterson
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC
| | - Amber R Smith
- Department of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - James T Neal
- Department of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Aaron K McCormick
- Department of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Calvin J Kuo
- Department of Medicine, Stanford University, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Christopher M Counter
- Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC
| | - Emanuel F Petricoin
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Adrienne D Cox
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kirsten L Bryant
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Channing J Der
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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19
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Li JT, Li KY, Su Y, Shen Y, Lei MZ, Zhang F, Yin M, Chen ZJ, Wen WY, Hu WG, Su D, Qu J, Lei QY. Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization. Natl Sci Rev 2021; 9:nwab212. [PMID: 35663242 PMCID: PMC9154341 DOI: 10.1093/nsr/nwab212] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/18/2021] [Accepted: 10/24/2021] [Indexed: 11/27/2022] Open
Abstract
BCAT2-mediated branched-chain amino acid (BCAA) catabolism is critical for pancreatic ductal adenocarcinoma (PDAC) development, especially at an early stage. However, whether a high-BCAA diet promotes PDAC development in vivo, and the underlying mechanism of BCAT2 upregulation, remain undefined. Here, we find that a high-BCAA diet promotes pancreatic intraepithelial neoplasia (PanIN) progression in LSL-KrasG12D/+; Pdx1-Cre (KC) mice. Moreover, we screened with an available deubiquitylase library which contains 31 members of USP family and identified that USP1 deubiquitylates BCAT2 at the K229 site. Furthermore, BCAA increases USP1 protein at the translational level via the GCN2-eIF2α pathway both in vitro and in vivo. More importantly, USP1 inhibition recedes cell proliferation and clone formation in PDAC cells and attenuates pancreas tumor growth in an orthotopic transplanted mice model. Consistently, a positive correlation between USP1 and BCAT2 is found in KC; LSL-KrasG12D/+; p53flox/+; Pdx1-Cre mice and clinical samples. Thus, a therapeutic targeting USP1-BCAT2-BCAA metabolic axis could be considered as a rational strategy for treatment of PDAC and precisive dietary intervention of BCAA has potentially translational significance.
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Affiliation(s)
- Jin-Tao Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Kai-Yue Li
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ying Su
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuan Shen
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ming-Zhu Lei
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fan Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Miao Yin
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zheng-Jun Chen
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Wen-Yu Wen
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wei-Guo Hu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Dan Su
- Cancer Research Institute, Zhejiang Cancer Hospital and Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang Province, Hangzhou, China
| | - Jia Qu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qun-Ying Lei
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Medical Epigenetics; International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
- Lead contact
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20
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Helenius IT, Madala HR, Yeh JRJ. An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate's Emerging Roles in Cell Proliferation and Survival. Biomolecules 2021; 11:1666. [PMID: 34827664 PMCID: PMC8615858 DOI: 10.3390/biom11111666] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 11/08/2021] [Accepted: 11/08/2021] [Indexed: 12/28/2022] Open
Abstract
A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate-aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, aspartate can become a limiting factor for tumor growth and cancer cell survival. Notably, aspartate availability has been associated with sensitivity or resistance to various therapeutics that are presently in the clinic or in clinical trials, arguing for a critical need for more effective aspartate-targeting approaches. In this review, we present current knowledge of the metabolic roles of aspartate in cancer cells and describe how cancer cells maintain aspartate levels under different metabolic states. We also highlight several promising aspartate level-modulating agents that are currently under investigation.
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Affiliation(s)
| | - Hanumantha Rao Madala
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA;
- Department of Medicine, Harvard Medical School, Boston, MA 02125, USA
| | - Jing-Ruey Joanna Yeh
- Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA;
- Department of Medicine, Harvard Medical School, Boston, MA 02125, USA
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21
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Li J, Chen X, Kang R, Zeh H, Klionsky DJ, Tang D. Regulation and function of autophagy in pancreatic cancer. Autophagy 2021; 17:3275-3296. [PMID: 33161807 PMCID: PMC8632104 DOI: 10.1080/15548627.2020.1847462] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/26/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter "autophagy") is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types and plays a complex role in pancreatic tumor biology, depending on various factors, such as tumor stage, microenvironment, immunometabolic state, and death signals. As a modulator connecting various cellular events, pharmacological targeting of nonselective autophagy may lead to both good and bad therapeutic effects. In contrast, targeting selective autophagy could reduce potential side effects of the drugs used. In this review, we describe the advances and challenges of autophagy in the development and therapy of pancreatic cancer.Abbreviations: AMPK: AMP-activated protein kinase; CQ: chloroquine; csc: cancer stem cells; DAMP: danger/damage-associated molecular pattern; EMT: epithelial-mesenchymal transition; lncRNA: long noncoding RNA; MIR: microRNA; PanIN: pancreatic intraepithelial neoplasia; PDAC: pancreatic ductal adenocarcinoma; PtdIns3K: phosphatidylinositol 3-kinase; SNARE: soluble NSF attachment protein receptor; UPS: ubiquitin-proteasome system.
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Affiliation(s)
- Jingbo Li
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Xin Chen
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Herbert Zeh
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
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22
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Stoof J, Harrold E, Mariottino S, Lowery MA, Walsh N. DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives. Front Cell Dev Biol 2021; 9:749490. [PMID: 34712667 PMCID: PMC8546202 DOI: 10.3389/fcell.2021.749490] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 09/22/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and survival rates have barely improved in decades. In the era of precision medicine, treatment strategies tailored to disease mutations have revolutionized cancer therapy. Next generation sequencing has found that up to a third of all PDAC tumors contain deleterious mutations in DNA damage repair (DDR) genes, highlighting the importance of these genes in PDAC. The mechanisms by which DDR gene mutations promote tumorigenesis, therapeutic response, and subsequent resistance are still not fully understood. Therefore, an opportunity exists to elucidate these processes and to uncover relevant therapeutic drug combinations and strategies to target DDR deficiency in PDAC. However, a constraint to preclinical research is due to limitations in appropriate laboratory experimental models. Models that effectively recapitulate their original cancer tend to provide high levels of predictivity and effective translation of preclinical findings to the clinic. In this review, we outline the occurrence and role of DDR deficiency in PDAC and provide an overview of clinical trials that target these pathways and the preclinical models such as 2D cell lines, 3D organoids and mouse models [genetically engineered mouse model (GEMM), and patient-derived xenograft (PDX)] used in PDAC DDR deficiency research.
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Affiliation(s)
- Jojanneke Stoof
- Trinity St. James Cancer Institute, Trinity College Dublin, Dublin, Ireland
| | - Emily Harrold
- Trinity College Dublin, Dublin, Ireland
- Mater Private Hospital, Dublin, Ireland
| | - Sarah Mariottino
- Trinity St. James Cancer Institute, Trinity College Dublin, Dublin, Ireland
| | - Maeve A Lowery
- Trinity St. James Cancer Institute, Trinity College Dublin, Dublin, Ireland
| | - Naomi Walsh
- National Institute of Cellular Biotechnology, School of Biotechnology, Dublin City University, Dublin, Ireland
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23
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Kocak M, Ezazi Erdi S, Jorba G, Maestro I, Farrés J, Kirkin V, Martinez A, Pless O. Targeting autophagy in disease: established and new strategies. Autophagy 2021; 18:473-495. [PMID: 34241570 PMCID: PMC9037468 DOI: 10.1080/15548627.2021.1936359] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Macroautophagy/autophagy is an evolutionarily conserved pathway responsible for clearing cytosolic aggregated proteins, damaged organelles or invading microorganisms. Dysfunctional autophagy leads to pathological accumulation of the cargo, which has been linked to a range of human diseases, including neurodegenerative diseases, infectious and autoimmune diseases and various forms of cancer. Cumulative work in animal models, application of genetic tools and pharmacologically active compounds, has suggested the potential therapeutic value of autophagy modulation in disease, as diverse as Huntington, Salmonella infection, or pancreatic cancer. Autophagy activation versus inhibition strategies are being explored, while the role of autophagy in pathophysiology is being studied in parallel. However, the progress of preclinical and clinical development of autophagy modulators has been greatly hampered by the paucity of selective pharmacological agents and biomarkers to dissect their precise impact on various forms of autophagy and cellular responses. Here, we summarize established and new strategies in autophagy-related drug discovery and indicate a path toward establishing a more efficient discovery of autophagy-selective pharmacological agents. With this knowledge at hand, modern concepts for therapeutic exploitation of autophagy might become more plausible. Abbreviations: ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related gene; AUTAC: autophagy-targeting chimera; CNS: central nervous system; CQ: chloroquine; GABARAP: gamma-aminobutyric acid type A receptor-associated protein; HCQ: hydroxychloroquine; LYTAC: lysosome targeting chimera; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NDD: neurodegenerative disease; PDAC: pancreatic ductal adenocarcinoma; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate; PROTAC: proteolysis-targeting chimera; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.
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Affiliation(s)
- Muhammed Kocak
- Cancer Research UK, Cancer Therapeutics Unit, the Institute of Cancer Research London, Sutton, UK
| | | | | | - Inés Maestro
- Centro De Investigaciones Biologicas "Margarita Salas"-CSIC, Madrid, Spain
| | | | - Vladimir Kirkin
- Cancer Research UK, Cancer Therapeutics Unit, the Institute of Cancer Research London, Sutton, UK
| | - Ana Martinez
- Centro De Investigaciones Biologicas "Margarita Salas"-CSIC, Madrid, Spain.,Centro De Investigación Biomédica En Red En Enfermedades Neurodegenerativas (CIBERNED), Instituto De Salud Carlos III, Madrid, Spain
| | - Ole Pless
- Fraunhofer ITMP ScreeningPort, Hamburg, Germany
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24
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Jia Y, Li HY, Wang Y, Wang J, Zhu JW, Wei YY, Lou L, Chen X, Mo SJ. Crosstalk between hypoxia-sensing ULK1/2 and YAP-driven glycolysis fuels pancreatic ductal adenocarcinoma development. Int J Biol Sci 2021; 17:2772-2794. [PMID: 34345207 PMCID: PMC8326115 DOI: 10.7150/ijbs.60018] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 06/13/2021] [Indexed: 12/29/2022] Open
Abstract
Autophagy and glycolysis are two catabolic processes that manipulate pancreatic ductal adenocarcinoma (PDAC) development in response to hypoxia sensing, yet the underlying mechanism of how they are interlinked remain elusive. Methods: The functional roles of Unc-51 like kinase 1 and 2 (ULK1/2) in pyruvate kinase M2 (PKM2) transcription and glycolysis under hypoxia were assessed by chromatin immunoprecipitation, luciferase reporter, glucose consumption and lactate production assay. Co-immunoprecipitation, cellular ubiquitination, His-pulldown, in vitro protein kinase assay, immunofluorescence, immunohistochemistry, CRISPR technology, in silico studies were adopted to determine the molecular mechanism. Correlation analyses were performed in KPC (Pdx1-Cre; LSL-KrasG12D/+; Trp53fl/+) mice and clinical samples from PDAC patients. Therapeutic potential of ULK1/2 inhibitor and 2-deoxyglucose (2-DG) or 3-bromopyruvate (3-BP) was evaluated in cell-derived xenograft (CDX) and the patient-derived xenograft (PDX) models of nude mice. Results: ULK1/2, but not ULK3, augments hypoxic glycolysis in PDAC cells mediated by PKM2 independent of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). Mechanistically, hypoxia stimulates ULK1 to translocate into nucleus, where it interacts with and phosphorylates yes-associated protein (YAP) at Ser227, resulting in YAP stabilization through blockade of ubiquitin-proteasome system (UPS), which in turn facilitates PKM2 transcription, glycolysis, cell proliferation in vitro as well as PDAC growth in mice. ULK1/2 is positively correlated with YAP and PKM2 in tumor tissues from KPC mice and clinical samples from PDAC patients. Pharmacological deactivation of ULK1/2 potentiates the antineoplastic efficacy of 2-DG and 3-BP in CDX and PDX models. Conclusion: Our findings underscore the Ser227 autophosphorylation-dependent nuclear YAP stabilization as a central node that couples ULK1/2-initiated autophagy to hypoxic glycolysis during PDAC development and propose that targeting ULK1/2 combined with 2-DG or 3-BP might be a feasible therapeutic strategy against PDAC.
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Affiliation(s)
- Yu Jia
- Cancer Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P.R.China
| | - Hui-Yan Li
- General Surgical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P.R.China
| | - Ying Wang
- Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R.China
| | - Jue Wang
- Department of Pathology, The First Affiliated Hospital, Sun Yet-Sen University, Guangzhou 510080, Guangdong, P.R.China
| | - Jing-Wen Zhu
- General Surgical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P.R.China
| | - Yan-Yan Wei
- General Surgical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P.R.China
| | - Lu Lou
- General Surgical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P.R.China
| | - Xing Chen
- General Surgical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P.R.China
| | - Shi-Jing Mo
- General Surgical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, P.R.China
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25
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Encarnación-Rosado J, Kimmelman AC. Harnessing metabolic dependencies in pancreatic cancers. Nat Rev Gastroenterol Hepatol 2021; 18:482-492. [PMID: 33742165 PMCID: PMC8249349 DOI: 10.1038/s41575-021-00431-7] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/16/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a 5-year survival rate of <10%. The tumour microenvironment (TME) of PDAC is characterized by excessive fibrosis and deposition of extracellular matrix, termed desmoplasia. This unique TME leads to high interstitial pressure, vascular collapse and low nutrient and oxygen diffusion. Together, these factors contribute to the unique biology and therapeutic resistance of this deadly tumour. To thrive in this hostile environment, PDAC cells adapt by using non-canonical metabolic pathways and rely on metabolic scavenging pathways such as autophagy and macropinocytosis. Here, we review the metabolic pathways that PDAC use to support their growth in the setting of an austere TME. Understanding how PDAC tumours rewire their metabolism and use scavenging pathways under environmental stressors might enable the identification of novel therapeutic approaches.
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Affiliation(s)
| | - Alec C Kimmelman
- Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
- Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA.
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26
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Abstract
Cells use mitophagy to remove dysfunctional or excess mitochondria, frequently in response to imposed stresses, such as hypoxia and nutrient deprivation. Mitochondrial cargo receptors (MCR) induced by these stresses target mitochondria to autophagosomes through interaction with members of the LC3/GABARAP family. There are a growing number of these MCRs, including BNIP3, BNIP3L, FUNDC1, Bcl2-L-13, FKBP8, Prohibitin-2, and others, in addition to mitochondrial protein targets of PINK1/Parkin phospho-ubiquitination. There is also an emerging link between mitochondrial lipid signaling and mitophagy where ceramide, sphingosine-1-phosphate, and cardiolipin have all been shown to promote mitophagy. Here, we review the upstream signaling mechanisms that regulate mitophagy, including components of the mitochondrial fission machinery, AMPK, ATF4, FoxOs, Sirtuins, and mtDNA release, and address the significance of these pathways for stress responses in tumorigenesis and metastasis. In particular, we focus on how mitophagy modulators intersect with cell cycle control and survival pathways in cancer, including following ECM detachment and during cell migration and metastasis. Finally, we interrogate how mitophagy affects tissue atrophy during cancer cachexia and therapy responses in the clinic.
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Affiliation(s)
- Logan P Poole
- The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, W-338, The University of Chicago, 929 E 57th Street, Chicago, IL, 60637, USA
- The Committee on Cancer Biology, The University of Chicago, Chicago, USA
| | - Kay F Macleod
- The Ben May Department for Cancer Research, The Gordon Center for Integrative Sciences, W-338, The University of Chicago, 929 E 57th Street, Chicago, IL, 60637, USA.
- The Committee on Cancer Biology, The University of Chicago, Chicago, USA.
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27
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Lysosomal Calcium Channels in Autophagy and Cancer. Cancers (Basel) 2021; 13:cancers13061299. [PMID: 33803964 PMCID: PMC8001254 DOI: 10.3390/cancers13061299] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/05/2021] [Accepted: 03/09/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Autophagy is a cellular self-eating process that uses lysosome, the waste disposal system of the cell, to degrade and recycle intracellular materials to maintain cellular homeostasis. Defects in autophagy are linked to a variety of pathological states, including cancer. Calcium is an important cellular messenger that regulates the survival of all animal cells. Alterations to calcium homoeostasis are associated with cancer. While it has long been considered as cellular recycling center, the lysosome is now widely known as an intracellular calcium store that regulates autophagy and cancer progression by releasing calcium via some ion channels residing in the lysosomal membrane. In this review, we summarize existing mechanisms of autophagy regulation by lysosomal calcium channels and their implications in cancer development. We hope to guide readers toward a more in-depth understanding of the importance of lysosomal calcium channels in cancer, and potentially facilitate the development of new therapeutics for some cancers. Abstract Ca2+ is pivotal intracellular messenger that coordinates multiple cell functions such as fertilization, growth, differentiation, and viability. Intracellular Ca2+ signaling is regulated by both extracellular Ca2+ entry and Ca2+ release from intracellular stores. Apart from working as the cellular recycling center, the lysosome has been increasingly recognized as a significant intracellular Ca2+ store that provides Ca2+ to regulate many cellular processes. The lysosome also talks to other organelles by releasing and taking up Ca2+. In lysosomal Ca2+-dependent processes, autophagy is particularly important, because it has been implicated in many human diseases including cancer. This review will discuss the major components of lysosomal Ca2+ stores and their roles in autophagy and human cancer progression.
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28
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GSK3B induces autophagy by phosphorylating ULK1. Exp Mol Med 2021; 53:369-383. [PMID: 33654220 PMCID: PMC8080724 DOI: 10.1038/s12276-021-00570-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 12/15/2020] [Accepted: 12/17/2020] [Indexed: 02/07/2023] Open
Abstract
Unc-51-like autophagy activating kinase 1 (ULK1), a mammalian homolog of the yeast kinase Atg1, has an essential role in autophagy induction. In nutrient and growth factor signaling, ULK1 activity is regulated by various posttranslational modifications, including phosphorylation, acetylation, and ubiquitination. We previously identified glycogen synthase kinase 3 beta (GSK3B) as an upstream regulator of insulin withdrawal-induced autophagy in adult hippocampal neural stem cells. Here, we report that following insulin withdrawal, GSK3B directly interacted with and activated ULK1 via phosphorylation of S405 and S415 within the GABARAP-interacting region. Phosphorylation of these residues facilitated the interaction of ULK1 with MAP1LC3B and GABARAPL1, while phosphorylation-defective mutants of ULK1 failed to do so and could not induce autophagy flux. Furthermore, high phosphorylation levels of ULK1 at S405 and S415 were observed in human pancreatic cancer cell lines, all of which are known to exhibit high levels of autophagy. Our results reveal the importance of GSK3B-mediated phosphorylation for ULK1 regulation and autophagy induction and potentially for tumorigenesis. Similar to cellular starvation conditions, insulin withdrawal may trigger the modification of an enzyme involved in the induction of autophagy, a key cellular recycling process. The ULK1 enzyme has a critical role in autophagy induction. Seong-Woon Yu at the Daegu Gyeongbuk Institute of Science and Technology, South Korea, and co-workers investigated how ULK1 is activated under insulin withdrawal condition. They found that another enzyme called GSK3B modifies two specific ULK1 amino acids, activating ULK1 and triggering autophagy. Further, they found high levels of this type of ULK1 modification in human pancreatic cancer cell lines that exhibited increased autophagy, suggesting possible implications for the development of certain cancerous tumors.
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29
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Moore AM, Zhou L, Cui J, Li L, Wu N, Yu A, Poddar S, Liang K, Abt ER, Kim S, Ghukasyan R, Khachatourian N, Pagano K, Elliott I, Dann AM, Riahi R, Le T, Dawson DW, Radu CG, Donahue TR. NAD + depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition. Proc Natl Acad Sci U S A 2021; 118:e2012469118. [PMID: 33597293 PMCID: PMC7923374 DOI: 10.1073/pnas.2012469118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.
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Affiliation(s)
- Alexandra M Moore
- Department of Surgery, University of California, Los Angeles, CA 90095
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Lei Zhou
- Department of Surgery, University of California, Los Angeles, CA 90095
- Department of Pancreatic and Thyroidal Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, China
| | - Jing Cui
- Department of Surgery, University of California, Los Angeles, CA 90095
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430022, China
| | - Luyi Li
- Department of Surgery, University of California, Los Angeles, CA 90095
| | - Nanping Wu
- Department of Surgery, University of California, Los Angeles, CA 90095
| | - Alice Yu
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Soumya Poddar
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095
- Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095
| | - Keke Liang
- Department of Surgery, University of California, Los Angeles, CA 90095
- Department of Pancreatic and Thyroidal Surgery, Shengjing Hospital, China Medical University, Shenyang 110004, China
| | - Evan R Abt
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095
- Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095
| | - Stephanie Kim
- Department of Surgery, University of California, Los Angeles, CA 90095
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Razmik Ghukasyan
- Department of Surgery, University of California, Los Angeles, CA 90095
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | | | - Kristina Pagano
- Department of Surgery, University of California, Los Angeles, CA 90095
| | - Irmina Elliott
- Department of Surgery, University of California, Los Angeles, CA 90095
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Amanda M Dann
- Department of Surgery, University of California, Los Angeles, CA 90095
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Rana Riahi
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095
| | - Thuc Le
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095
- Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095
| | - David W Dawson
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095
| | - Caius G Radu
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095
- Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095
| | - Timothy R Donahue
- Department of Surgery, University of California, Los Angeles, CA 90095;
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095
- Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095
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30
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Rai V, Agrawal S. Targets (Metabolic Mediators) of Therapeutic Importance in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2020; 21:E8502. [PMID: 33198082 PMCID: PMC7697422 DOI: 10.3390/ijms21228502] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive invasive cancer, is the fourth most common cause of cancer-related death in the United States. The higher mortality in PDAC is often attributed to the inability to detect it until it has reached advanced stages. The major challenge in tackling PDAC is due to its elusive pathology, minimal effectiveness, and resistance to existing therapeutics. The aggressiveness of PDAC is due to the capacity of tumor cells to alter their metabolism, utilize the diverse available fuel sources to adapt and grow in a hypoxic and harsh environment. Therapeutic resistance is due to the presence of thick stroma with poor angiogenesis, thus making drug delivery to tumor cells difficult. Investigating the metabolic mediators and enzymes involved in metabolic reprogramming may lead to the identification of novel therapeutic targets. The metabolic mediators of glucose, glutamine, lipids, nucleotides, amino acids and mitochondrial metabolism have emerged as novel therapeutic targets. Additionally, the role of autophagy, macropinocytosis, lysosomal transport, recycling, amino acid transport, lipid transport, and the role of reactive oxygen species has also been discussed. The role of various pro-inflammatory cytokines and immune cells in the pathogenesis of PDAC and the metabolites involved in the signaling pathways as therapeutic targets have been previously discussed. This review focuses on the therapeutic potential of metabolic mediators in PDAC along with stemness due to metabolic alterations and their therapeutic importance.
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Affiliation(s)
- Vikrant Rai
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Swati Agrawal
- Department of Surgery, Creighton University School of Medicine, Omaha, NE 68178, USA;
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31
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Understanding metabolomic characteristics of pancreatic ductal adenocarcinoma by HR-MAS NMR detection of pancreatic tissues. J Pharm Biomed Anal 2020; 190:113546. [DOI: 10.1016/j.jpba.2020.113546] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/07/2020] [Accepted: 08/08/2020] [Indexed: 12/13/2022]
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32
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Mitochondria-targeted magnolol inhibits OXPHOS, proliferation, and tumor growth via modulation of energetics and autophagy in melanoma cells. Cancer Treat Res Commun 2020; 25:100210. [PMID: 32987287 PMCID: PMC7883397 DOI: 10.1016/j.ctarc.2020.100210] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 09/01/2020] [Accepted: 09/15/2020] [Indexed: 12/19/2022]
Abstract
Introduction: Melanoma is an aggressive form of skin cancer for which there are no effective drugs for prolonged treatment. The existing kinase inhibitor antiglycolytic drugs (B-Raf serine/threonine kinase or BRAF inhibitors) are effective for a short time followed by a rapid onset of drug resistance. Presentation of case: Here, we show that a mitochondria-targeted analog of magnolol, Mito-magnolol (Mito-MGN), inhibits oxidative phosphorylation (OXPHOS) and proliferation of melanoma cells more potently than untargeted magnolol. Mito-MGN also inhibited tumor growth in murine melanoma xenografts. Mito-MGN decreased mitochondrial membrane potential and modulated energetic and mitophagy signaling proteins. Discussion: Results indicate that Mito-MGN is significantly more potent than the FDA-approved OXPHOS inhibitor in inhibiting proliferation of melanoma cells. Conclusion: These findings have implications in the treatment of melanomas with enhanced OXPHOS status due to metabolic reprogramming or drug resistance.
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33
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Eloranta K, Cairo S, Liljeström E, Soini T, Kyrönlahti A, Judde JG, Wilson DB, Heikinheimo M, Pihlajoki M. Chloroquine Triggers Cell Death and Inhibits PARPs in Cell Models of Aggressive Hepatoblastoma. Front Oncol 2020; 10:1138. [PMID: 32766148 PMCID: PMC7379510 DOI: 10.3389/fonc.2020.01138] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/05/2020] [Indexed: 12/28/2022] Open
Abstract
Background: Hepatoblastoma (HB) is the most common pediatric liver malignancy. Despite advances in chemotherapeutic regimens and surgical techniques, the survival of patients with advanced HB remains poor, underscoring the need for new therapeutic approaches. Chloroquine (CQ), a drug used to treat malaria and rheumatologic diseases, has been shown to inhibit the growth and survival of various cancer types. We examined the antineoplastic activity of CQ in cell models of aggressive HB. Methods: Seven human HB cell models, all derived from chemoresistant tumors, were cultured as spheroids in the presence of relevant concentrations of CQ. Morphology, viability, and induction of apoptosis were assessed after 48 and 96 h of CQ treatment. Metabolomic analysis and RT-qPCR based Death Pathway Finder array were used to elucidate the molecular mechanisms underlying the CQ effect in a 2-dimensional cell culture format. Quantitative western blotting was performed to validate findings at the protein level. Results: CQ had a significant dose and time dependent effect on HB cell viability both in spheroids and in 2-dimensional cell cultures. Following CQ treatment HB spheroids exhibited increased caspase 3/7 activity indicating the induction of apoptotic cell death. Metabolomic profiling demonstrated significant decreases in the concentrations of NAD+ and aspartate in CQ treated cells. In further investigations, oxidation of NAD+ decreased as consequence of CQ treatment and NAD+/NADH balance shifted toward NADH. Aspartate supplementation rescued cells from CQ induced cell death. Additionally, downregulated expression of PARP1 and PARP2 was observed. Conclusions: CQ treatment inhibits cell survival in cell models of aggressive HB, presumably by perturbing NAD+ levels, impairing aspartate bioavailability, and inhibiting PARP expression. CQ thus holds potential as a new agent in the management of HB.
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Affiliation(s)
- Katja Eloranta
- Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | | | - Emmi Liljeström
- Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Tea Soini
- Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Antti Kyrönlahti
- Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | | | - David B Wilson
- Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States.,Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
| | - Markku Heikinheimo
- Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, United States
| | - Marjut Pihlajoki
- Pediatric Research Center, Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
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34
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The Ras-ERK1/2 signaling pathway regulates H3K9ac through PCAF to promote the development of pancreatic cancer. Life Sci 2020; 256:117936. [PMID: 32531376 DOI: 10.1016/j.lfs.2020.117936] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 05/21/2020] [Accepted: 06/07/2020] [Indexed: 12/11/2022]
Abstract
AIMS The regulation of the Ras-ERK pathway is the crucial point in pancreatic carcinogenesis, and the Ras kinase is an essential regulatory upstream signal molecule of the ERK1/2 pathway. H3K9ac is a vital histone modification, but its specific role in pancreatic cancer remains unclear. This research aims to study whether the modification level of H3K9ac can regulate the characteristic phenotype of the pancreatic cancer cells by affecting the downstream expression, proliferation, migration, and other related genes. MAIN METHODS The RasG12V/T35S were used to transfect pancreatic cancer cells, and the levels of phosphorylated ERK1/2 and H3K9ac were detected by western blotting. The colony formation assay, transwell assay, and chromatin immunoprecipitation assay were used to study cell viability, migration, and the downstream genes of the ERK1/2 pathway. KEY FINDINGS The results showed that Ras ERK1/2 reduced H3K9ac expression in ASPC-1 cells, and H3K9ac significantly repressed the viability of cells, colony formation, and ASPC-1 cell movement induced by Ras ERK1/2. Besides, HDAC1 silencing increased H3K9ac expression, and changed the effect of Ras ERK1/2 on ASPC-1 cells proliferation, its movement, and mRNAs of ERK1/2 downstream genes. Moreover, Ras ERK1/2 inhibited H3K9ac expression by the degradation of PCAF via MDM2. SIGNIFICANCE Ras ERK1/2 promotes pancreatic carcinogenesis cell movement, through down-regulating H3K9ac via MDM2 mediated PCAF degradation.
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35
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Tong L, Wang X, Chen Z, Liang Y, Yang Y, Gao W, Liu Z, Tang B. One-Step Fabrication of Functional Carbon Dots with 90% Fluorescence Quantum Yield for Long-Term Lysosome Imaging. Anal Chem 2020; 92:6430-6436. [DOI: 10.1021/acs.analchem.9b05553] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Lili Tong
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Xiuxiu Wang
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Zhenzhen Chen
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Yuhua Liang
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Yapei Yang
- Key Laboratory of Oral Maxillofacial-Head and Neck Medical Biology of Shandong Province, Liaocheng People’s Hospital, Liaocheng, Shandong 252000, P. R. China
| | - Wen Gao
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Zhenhua Liu
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Biomedical Sciences, Shandong Normal University, Jinan, Shandong 250014, P.R. China
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36
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Gorecki L, Andrs M, Rezacova M, Korabecny J. Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy. Pharmacol Ther 2020; 210:107518. [PMID: 32109490 DOI: 10.1016/j.pharmthera.2020.107518] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023]
Abstract
Chemoresistance, radioresistance, and the challenge of achieving complete resection are major driving forces in the search for more robust and targeted anticancer therapies. Targeting the DNA damage response has recently attracted research interest, as these processes are enhanced in tumour cells. The major replication stress responder is ATM and Rad3-related (ATR) kinase, which is attracting attention worldwide with four drug candidates currently in phase I/II clinical trials. This review addresses a potent and selective small-molecule ATR inhibitor, which is known as VX-970 (also known as berzosertib or M6620), and summarizes the existing preclinical data to provide deep insight regarding its real potential. We also outline the transition from preclinical to clinical studies, as well as its relationships with other clinical candidates (AZD6738, VX-803 [M4344], and BAY1895344). The results suggest that VX-970 is indeed a promising anticancer drug that can be used both as monotherapy and in combination with either chemotherapy or radiotherapy strategies. Based on patient anamnesis and biomarker identification, VX-970 could become a valuable tool for oncologists in the fight against cancer.
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Affiliation(s)
- Lukas Gorecki
- Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
| | - Martin Andrs
- Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic
| | - Martina Rezacova
- Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Simkova 870, 500 38 Hradec Kralove, Czech Republic
| | - Jan Korabecny
- Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
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37
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Lu X, Fu H, Chen R, Wang Y, Zhan Y, Song G, Hu T, Xia C, Tian X, Zhang B. Phosphoinositide specific phospholipase Cγ1 inhibition-driven autophagy caused cell death in human lung adenocarcinoma A549 cells in vivo and in vitro. Int J Biol Sci 2020; 16:1427-1440. [PMID: 32210730 PMCID: PMC7085223 DOI: 10.7150/ijbs.42962] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022] Open
Abstract
Our previous studies indicated that phosphoinositide specific phospholipase Cγ1 (PLCγ1) was involved in autophagy induction in colon and hepatic carcinoma cells. However, whether and how PLCγ1 regulation in human lung adenocarcinoma is linked to autophagy remains unclear. Here, we assessed the protein expression of PLCγ1 in human lung adenocarcinoma tissue using immunohistochemistry assay and the relationship between PLCG1 and autophagy in The Cancer Genome Atlas Network (TCGA) using Spearman correlation analysis and GSEA software. Furthermore, the interaction between PLCγ1 and autophagy-related signal molecules was investigated in human lung adenocarcinoma A549 cells treated with different inhibitors or transduction with lentivirus-mediated PLCγ1 gene short-hairpin RNA (shRNA) vectors using MTT, clonogenicity, Transwell migration, RT-PCR, Caspase-3, mitochondrial transmembrane potential, and western blotting assays, as well as transmission electron microscope technique. Additionally, the effect of shRNA/PLCγ1 alone or combined with autophagic activator Lithium Chloride (LiCl) on tumor growth and metastasis was measured using immunohistochemistry and assays in A549 xenograft nude mouse model. The results showed that increased PLCγ1 expression occurred frequently in human lung adenocarcinoma tissue with higher grades of T in TNM staging classification. PLCγ1 significantly enriched in autophagic process and regulation, which negatively regulating autophagy was enriched in higher expression of PLCγ1. PLCγ1 inhibition partially reduced cell proliferation and migration of A549 cells, with an increased autophagic flux involving alterations of AMPKα, mTOR, and ERK levels. However, PLCγ1 inhibition-driven autophagy led to cell death without depending on Caspase-3 and RIP1. Additionally, the abrogation of PLCγ1 signaling by shRNA and combination with autophagic activator LiCl could efficaciously suppress tumor growth and metastasis in A549 xenograft nude mice, in combination with a decrease in P62 level. These findings collectively suggest that reduction of cell proliferation and migration by PLCγ1 inhibition could be partially attributed to PLCγ1 inhibition-driven autophagic cell death (ACD). It highlights the potential role of a combination between targeting PLCγ1 and autophagy pathway in anti-tumor therapy, which may be an efficacious new strategy to overcome the autophagy addition of tumor and acquired resistance to current therapy.
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Affiliation(s)
- Xiaohong Lu
- Cancer Research Center, School of Medicine, Xiamen University, 361102, Fujian, China
| | - Haijing Fu
- Cancer Research Center, School of Medicine, Xiamen University, 361102, Fujian, China
| | - Rui Chen
- Cancer Research Center, School of Medicine, Xiamen University, 361102, Fujian, China
| | - Yue Wang
- Zhongshan Hospital, Xiamen University,361004, Xiamen, Fujian, China
| | - Yanyan Zhan
- Cancer Research Center, School of Medicine, Xiamen University, 361102, Fujian, China
| | - Gang Song
- Cancer Research Center, School of Medicine, Xiamen University, 361102, Fujian, China
| | - Tianhui Hu
- Cancer Research Center, School of Medicine, Xiamen University, 361102, Fujian, China
| | - Chun Xia
- Zhongshan Hospital, Xiamen University,361004, Xiamen, Fujian, China
| | - Xuemei Tian
- School of Life Sciences, South China Normal University, 510631, Guangzhou, Gangdong, China
| | - Bing Zhang
- Cancer Research Center, School of Medicine, Xiamen University, 361102, Fujian, China
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Kim SS, Xu S, Cui J, Poddar S, Le TM, Hayrapetyan H, Li L, Wu N, Moore AM, Zhou L, Yu AC, Dann AM, Elliott IA, Abt ER, Kim W, Dawson DW, Radu CG, Donahue TR. Histone deacetylase inhibition is synthetically lethal with arginine deprivation in pancreatic cancers with low argininosuccinate synthetase 1 expression. Theranostics 2020; 10:829-840. [PMID: 31903153 PMCID: PMC6929997 DOI: 10.7150/thno.40195] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/05/2019] [Indexed: 01/10/2023] Open
Abstract
Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.
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39
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New M, Tooze S. The Role of Autophagy in Pancreatic Cancer-Recent Advances. BIOLOGY 2019; 9:E7. [PMID: 31905604 PMCID: PMC7169408 DOI: 10.3390/biology9010007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/23/2019] [Accepted: 12/26/2019] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.
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Affiliation(s)
| | - Sharon Tooze
- Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London NW1 1AT, UK;
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40
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Yan L, Raj P, Yao W, Ying H. Glucose Metabolism in Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11101460. [PMID: 31569510 PMCID: PMC6826406 DOI: 10.3390/cancers11101460] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/25/2019] [Accepted: 09/25/2019] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with a five-year survival rate of around 5% to 8%. To date, very few available drugs have been successfully used to treat PDAC due to the poor understanding of the tumor-specific features. One of the hallmarks of pancreatic cancer cells is the deregulated cellular energetics characterized by the “Warburg effect”. It has been known for decades that cancer cells have a dramatically increased glycolytic flux even in the presence of oxygen and normal mitochondrial function. Glycolytic flux is the central carbon metabolism process in all cells, which not only produces adenosine triphosphate (ATP) but also provides biomass for anabolic processes that support cell proliferation. Expression levels of glucose transporters and rate-limiting enzymes regulate the rate of glycolytic flux. Intermediates that branch out from glycolysis are responsible for redox homeostasis, glycosylation, and biosynthesis. Beyond enhanced glycolytic flux, pancreatic cancer cells activate nutrient salvage pathways, which includes autophagy and micropinocytosis, from which the generated sugars, amino acids, and fatty acids are used to buffer the stresses induced by nutrient deprivation. Further, PDAC is characterized by extensive metabolic crosstalk between tumor cells and cells in the tumor microenvironment (TME). In this review, we will give an overview on recent progresses made in understanding glucose metabolism-related deregulations in PDAC.
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Affiliation(s)
- Liang Yan
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Priyank Raj
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Wantong Yao
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Haoqiang Ying
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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Chiang CF, Hsu YH, Liu CC, Liang PC, Miaw SC, Lin WL. Pulsed-wave Ultrasound Hyperthermia Enhanced Nanodrug Delivery Combined with Chloroquine Exerts Effective Antitumor Response and Postpones Recurrence. Sci Rep 2019; 9:12448. [PMID: 31462676 PMCID: PMC6713759 DOI: 10.1038/s41598-019-47345-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 06/28/2019] [Indexed: 12/23/2022] Open
Abstract
Autophagy is found to serve as a surviving mechanism for cancer cells. Inhibiting autophagy has been considered as an adjuvant anti-cancer strategy. In this study, we investigated the anti-tumor effect of combining pulsed-wave ultrasound hyperthermia (pUH) enhanced PEGylated liposomal doxorubicin (PLD) delivery with an autophagy inhibitor chloroquine (CQ). BALB/c mice bearing subcutaneous 4T1 tumor received intravenous injection of PLD (10 mg/kg) plus 15-minute on-tumor pUH on Day 5 after tumor implantation and were then fed with CQ (50 mg/kg daily) thereafter. Prolonged suppression of tumor growth was attained with PLD + pUH + CQ treatment, whereas in PLD + pUH group tumors quickly recurred after an initial inhibition. Treatment with CQ monotherapy had no benefit compared to the control group. Immunohistochemical staining and Western blotting showed that autophagy of cancer cells was blocked for the mice receiving CQ. It indicates that PLD + pUH + CQ is a promising strategy to treat cancer for a long-term inhibition.
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Affiliation(s)
- Chi-Feng Chiang
- Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan
| | - Yu-Hone Hsu
- Division of Neurosurgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chih-Chun Liu
- Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.,Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Po-Chin Liang
- Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.,Department of Radiology, Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan
| | - Shi-Chuen Miaw
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Win-Li Lin
- Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan. .,Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan.
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