|
1
|
Bu J, Miao Z, Yang Q. GOT2: New therapeutic target in pancreatic cancer. Genes Dis 2025; 12:101370. [PMID: 40247913 PMCID: PMC12005923 DOI: 10.1016/j.gendis.2024.101370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 04/18/2024] [Accepted: 06/21/2024] [Indexed: 04/19/2025] Open
Abstract
In recent years, the incidence and mortality rates of pancreatic cancer have been steadily increasing, and conventional therapies have shown a high degree of tolerance. Therefore, the search for new therapeutic targets remains a key issue in current research. Mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) is an important component of the malate-aspartate shuttle system, which plays an important role in the maintenance of cellular redox balance and amino acid metabolism, and has the potential to become a promising target for anti-cancer therapy. In this paper, we will elaborate on the metabolic and immune effects of GOT2 in pancreatic cancer based on existing studies, with a view to opening up new avenues for the treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Jiarui Bu
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Zeyu Miao
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Qing Yang
- Department of Pathogenobiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| |
Collapse
|
|
2
|
Cho HJ, Yoo J, Choi RJ, Lee JS, Kim RN, Park J, Moon JH, Kim EH, Teo WY, Chang JH, Kim SY, Kang SG. N-phenylmaleimide induces bioenergetic switch and suppresses tumor growth in glioblastoma tumorspheres by inhibiting SLC25A11. Cancer Cell Int 2025; 25:184. [PMID: 40405188 PMCID: PMC12096590 DOI: 10.1186/s12935-025-03813-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 05/08/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND Glioblastoma (GBM) is a highly resistant tumor, and targeting its bioenergetics could be a potential treatment strategy. GBM cells depend on cytosolic nicotinamide adenine dinucleotide (NADH), which is transported into the mitochondria via the malate-aspartate shuttle (MAS) for ATP production. N-phenylmaleimide (KN612) is a MAS inhibitor that targets SLC25A11, an antiporter protein of the MAS. Therefore, this study investigated the effects of KN612 in GBM treatment using in vitro and in vivo models. METHODS We examined the biological effects of KN612 in GBM tumorspheres (TSs), including its effects on cell viability, ATP level, cell cycle, stemness, invasive properties, energy metabolic pathways, and transcriptomes. Additionally, we investigated the in vivo efficacy of KN612 in a mouse orthotopic xenograft model. RESULTS Transcriptomic analysis showed that SLC25A11 mRNA expression was significantly higher in GBM TSs than in normal human astrocytes. Additionally, siRNA-mediated SLC25A11 knockdown and KN612-mediated MAS inhibition decreased the oxygen consumption rate, ATP levels, mitochondrial activity, and cell viability in GBM TSs and decreased the stemness and invasion ability of GBM cells. Moreover, gene ontology functional annotation indicated that KN612 treatment inhibited cell-cycle and mitotic processes. Furthermore, KN612 treatment reduced tumor size and prolonged survival in an orthotopic xenograft model. CONCLUSIONS Targeting GBM bioenergetics using KN612 may represent a novel and effective approach for GBM treatment.
Collapse
Affiliation(s)
- Hye Joung Cho
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jihwan Yoo
- Department of Neurosurgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of Medical Science, Yonsei University Graduate School, Seoul, Republic of Korea
| | - Ran Joo Choi
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Seon Lee
- Department of Division of Cancer Biology, National Cancer Center, Goyang, Republic of Korea
| | - Ryong Nam Kim
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Junseong Park
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
- Department of College of Medicine, The Catholic University of Korea, Catholic Medical Center, Seoul, Republic of Korea
| | - Ju Hyung Moon
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eui Hyun Kim
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Wan-Yee Teo
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore
- Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore
| | - Jong Hee Chang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo-Youl Kim
- Department of Division of Cancer Biology, National Cancer Center, Goyang, Republic of Korea
| | - Seok-Gu Kang
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Brain Tumor Translational Research Laboratory, Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
- Department of Medical Science, Yonsei University Graduate School, Seoul, Republic of Korea.
- Brain Research Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| |
Collapse
|
|
3
|
Peng H, Dou H, He S, Xie YA, Zhang Q, Zheng J. The role of GOT1 in cancer metabolism. Front Oncol 2024; 14:1519046. [PMID: 39777342 PMCID: PMC11703747 DOI: 10.3389/fonc.2024.1519046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
GOT1, a cytoplasmic glutamic oxaloacetic transaminase, plays a critical role in various metabolic pathways essential for cellular homeostasis and dysregulated metabolism. Recent studies have highlighted the significant plasticity and roles of GOT1 in metabolic reprogramming through participating in both classical and non-classical glutamine metabolism, glycolytic metabolism, and other metabolic pathways. This review summarizes emerging insights on the metabolic roles of GOT1 in cancer cells and emphasizes the response of cancer cells to altered metabolism when the expression of GOT1 is altered. We review how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT1 is inhibited and delineate the molecular mechanisms of GOT1's interaction with specific oncogenes and regulators at multiple levels, including transcriptional and epigenetic regulation, which govern cellular growth and metabolism. These insights may provide new directions for cancer metabolism research and novel targets for cancer treatment.
Collapse
Affiliation(s)
- Huan Peng
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Huihong Dou
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Sheng He
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects Research and Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yu-an Xie
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Qinle Zhang
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Birth Defects and Stem Cell Biobank, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jianqiu Zheng
- Birth Defects Prevention and Control Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Key Laboratory of Reproductive Health and Birth Defect Prevention, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Guangxi Clinical Research Center for Pediatric Diseases, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| |
Collapse
|
|
4
|
Jeroundi N, Roy C, Basset L, Pignon P, Preisser L, Blanchard S, Bocca C, Abadie C, Lalande J, Gueguen N, Mabilleau G, Lenaers G, Moreau A, Copin MC, Tcherkez G, Delneste Y, Couez D, Jeannin P. Glycogenesis and glyconeogenesis from glutamine, lactate and glycerol support human macrophage functions. EMBO Rep 2024; 25:5383-5407. [PMID: 39424955 PMCID: PMC11624281 DOI: 10.1038/s44319-024-00278-4] [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: 10/06/2023] [Revised: 09/03/2024] [Accepted: 09/15/2024] [Indexed: 10/21/2024] Open
Abstract
Macrophages fight infection and ensure tissue repair, often operating at nutrient-poor wound sites. We investigated the ability of human macrophages to metabolize glycogen. We observed that the cytokines GM-CSF and M-CSF plus IL-4 induced glycogenesis and the accumulation of glycogen by monocyte-derived macrophages. Glyconeogenesis occurs in cells cultured in the presence of the inflammatory cytokines GM-CSF and IFNγ (M1 cells), via phosphoenolpyruvate carboxykinase 2 (PCK2) and fructose-1,6-bisphosphatase 1 (FBP1). Enzyme inhibition with drugs or gene silencing techniques and 13C-tracing demonstrate that glutamine (metabolized by the TCA cycle), lactic acid, and glycerol were substrates of glyconeogenesis only in M1 cells. Tumor-associated macrophages (TAMs) also store glycogen and can perform glyconeogenesis. Finally, macrophage glycogenolysis and the pentose phosphate pathway (PPP) support cytokine secretion and phagocytosis regardless of the availability of extracellular glucose. Thus, glycogen metabolism supports the functions of human M1 and M2 cells, with inflammatory M1 cells displaying a possible dependence on glyconeogenesis.
Collapse
Affiliation(s)
- Najia Jeroundi
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
| | - Charlotte Roy
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
| | - Laetitia Basset
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
| | - Pascale Pignon
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
| | - Laurence Preisser
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
| | - Simon Blanchard
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
- Immunology and Allergology laboratory, University Hospital, Angers, France
| | - Cinzia Bocca
- Univ Angers, Inserm, CNRS, MitoVasc, SFR ICAT, F-49000, Angers, France
- Department of Genetics and Biochemistry, University Hospital, Angers, France
| | - Cyril Abadie
- Univ Angers, INRAe, IRHS, SFR QUASAV, F-49000, Angers, France
| | - Julie Lalande
- Univ Angers, INRAe, IRHS, SFR QUASAV, F-49000, Angers, France
| | - Naïg Gueguen
- Univ Angers, Inserm, CNRS, MitoVasc, SFR ICAT, F-49000, Angers, France
- Department of Genetics and Biochemistry, University Hospital, Angers, France
| | - Guillaume Mabilleau
- Univ Angers, Nantes Université, Inserm, Oniris, RMeS, SFR ICAT, F-49000, Angers, France
- Department of Cell and Tissue Pathology, University Hospital, Angers, France
| | - Guy Lenaers
- Univ Angers, Inserm, CNRS, MitoVasc, SFR ICAT, F-49000, Angers, France
- Department of Genetics and Biochemistry, University Hospital, Angers, France
| | - Aurélie Moreau
- Inserm, Nantes Université, University Hospital of Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Nantes, France
| | - Marie-Christine Copin
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
- Department of Cell and Tissue Pathology, University Hospital, Angers, France
| | - Guillaume Tcherkez
- Univ Angers, INRAe, IRHS, SFR QUASAV, F-49000, Angers, France
- Research School of Biology, ANU College of Science, Australian National University, Canberra, ACT, 2601, Australia
| | - Yves Delneste
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
- Immunology and Allergology laboratory, University Hospital, Angers, France
| | - Dominique Couez
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France
| | - Pascale Jeannin
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, LabEx IGO, F-49000, Angers, France.
- Immunology and Allergology laboratory, University Hospital, Angers, France.
| |
Collapse
|
|
5
|
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.
Collapse
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.
| |
Collapse
|
|
6
|
Kim M, Hwang S, Jeong SM. Targeting cellular adaptive responses to glutaminolysis perturbation for cancer therapy. Mol Cells 2024; 47:100096. [PMID: 39038517 PMCID: PMC11342766 DOI: 10.1016/j.mocell.2024.100096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/11/2024] [Accepted: 07/16/2024] [Indexed: 07/24/2024] Open
Abstract
Metabolic aberrations, notably deviations in glutamine metabolism, are crucial in the oncogenic process, offering vital resources for the unlimited proliferation and enhanced survival capabilities of cancer cells. The dependency of malignant cells on glutamine metabolism has led to the proposition of targeted therapeutic strategies. However, the capability of cancer cells to initiate adaptive responses undermines the efficacy of these therapeutic interventions. This review meticulously examines the multifaceted adaptive mechanisms that cancer cells deploy to sustain survival and growth following the disruption of glutamine metabolism. Emphasis is placed on the roles of transcription factors, alterations in metabolic pathways, the mechanistic target of rapamycin complex 1 signaling axis, autophagy, macropinocytosis, nucleotide biosynthesis, and the scavenging of ROS. Thus, the delineation and subsequent targeting of these adaptive responses in the context of therapies aimed at glutamine metabolism offer a promising avenue for circumventing drug resistance in cancer treatment.
Collapse
Affiliation(s)
- Minjoong Kim
- Department of Biochemistry, Institute for Aging and Metabolic Diseases, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Sunsook Hwang
- Department of Biochemistry, Institute for Aging and Metabolic Diseases, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Seung Min Jeong
- Department of Biochemistry, Institute for Aging and Metabolic Diseases, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.
| |
Collapse
|
|
7
|
Zhang L, Wu Z, Qiu X, Zhang J, Cheng SC. Glutamate oxaloacetate transaminase 1 is dispensable in macrophage differentiation and anti-pathogen response. Commun Biol 2024; 7:817. [PMID: 38965342 PMCID: PMC11224350 DOI: 10.1038/s42003-024-06479-w] [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: 10/29/2023] [Accepted: 06/21/2024] [Indexed: 07/06/2024] Open
Abstract
Macrophages play a pivotal role in orchestrating the immune response against pathogens. While the intricate interplay between macrophage activation and metabolism remains a subject of intense investigation, the role of glutamate oxaloacetate transaminase 1 (Got1) in this context has not been extensively assessed. Here, we investigate the impact of Got1 on macrophage polarization and function, shedding light on its role in reactive oxygen species (ROS) production, pathogen defense, and immune paralysis. Using genetically modified mouse models, including both myeloid specific knockout and overexpression, we comprehensively demonstrate that Got1 depletion leads to reduced ROS production in macrophages. Intriguingly, this impairment in ROS generation does not affect the resistance of Got1 KO mice to pathogenic challenges. Furthermore, Got1 is dispensable for M2 macrophage differentiation and does not influence the onset of LPS-induced immune paralysis. Our findings underscore the intricate facets of macrophage responses, suggesting that Got1 is dispensable in discrete immunological processes.
Collapse
Affiliation(s)
- Lishan Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Zhengyi Wu
- State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Xuanhui Qiu
- State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Jia Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Shih-Chin Cheng
- State Key Laboratory of Cellular Stress Biology, School of Life Science, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
| |
Collapse
|
|
8
|
Gu M, Liu Y, Xin P, Guo W, Zhao Z, Yang X, Ma R, Jiao T, Zheng W. Fundamental insights and molecular interactions in pancreatic cancer: Pathways to therapeutic approaches. Cancer Lett 2024; 588:216738. [PMID: 38401887 DOI: 10.1016/j.canlet.2024.216738] [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: 01/08/2024] [Revised: 02/08/2024] [Accepted: 02/18/2024] [Indexed: 02/26/2024]
Abstract
The gastrointestinal tract can be affected by a number of diseases that pancreatic cancer (PC) is a malignant manifestation of them. The prognosis of PC patients is unfavorable and because of their diagnosis at advanced stage, the treatment of this tumor is problematic. Owing to low survival rate, there is much interest towards understanding the molecular profile of PC in an attempt in developing more effective therapeutics. The conventional therapeutics for PC include surgery, chemotherapy and radiotherapy as well as emerging immunotherapy. However, PC is still incurable and more effort should be performed. The molecular landscape of PC is an underlying factor involved in increase in progression of tumor cells. In the presence review, the newest advances in understanding the molecular and biological events in PC are discussed. The dysregulation of molecular pathways including AMPK, MAPK, STAT3, Wnt/β-catenin and non-coding RNA transcripts has been suggested as a factor in development of tumorigenesis in PC. Moreover, cell death mechanisms such as apoptosis, autophagy, ferroptosis and necroptosis demonstrate abnormal levels. The EMT and glycolysis in PC cells enhance to ensure their metastasis and proliferation. Furthermore, such abnormal changes have been used to develop corresponding pharmacological and nanotechnological therapeutics for PC.
Collapse
Affiliation(s)
- Ming Gu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Yang Liu
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Peng Xin
- Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Zimo Zhao
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Xu Yang
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Ruiyang Ma
- Department of Otorhinolaryngology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Taiwei Jiao
- Department of Gastroenterology and Endoscopy, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| | - Wenhui Zheng
- Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
| |
Collapse
|
|
9
|
Siwo GH, Singal AG, Waljee AK. Pan-cancer molecular signatures connecting aspartate transaminase (AST) to cancer prognosis, metabolic and immune signatures. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.01.582939. [PMID: 38496547 PMCID: PMC10942358 DOI: 10.1101/2024.03.01.582939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Background Serum aspartate transaminase (sAST) level is used routinely in conjunction with other clinical assays to assess liver health and disease. Increasing evidence suggests that sAST is associated with all-cause mortality and has prognostic value in several cancers, including gastrointestinal and urothelial cancers. Here, we undertake a systems approach to unravel molecular connections between AST and cancer prognosis, metabolism, and immune signatures at the transcriptomic and proteomic levels. Methods We mined public gene expression data across multiple normal and cancerous tissues using the Genotype Tissue Expression (GTEX) resource and The Cancer Genome Atlas (TCGA) to assess the expression of genes encoding AST isoenzymes (GOT1 and GOT2) and their association with disease prognosis and immune infiltration signatures across multiple tumors. We examined the associations between AST and previously reported pan-cancer molecular subtypes characterized by distinct metabolic and immune signatures. We analyzed human protein-protein interaction networks for interactions between GOT1 and GOT2 with cancer-associated proteins. Using public databases and protein-protein interaction networks, we determined whether the subset of proteins that interact with AST (GOT1 and GOT2 interactomes) are enriched with proteins associated with specific diseases, miRNAs and transcription factors. Results We show that AST transcript isoforms (GOT1 and GOT2) are expressed across a wide range of normal tissues. AST isoforms are upregulated in tumors of the breast, lung, uterus, and thymus relative to normal tissues but downregulated in tumors of the liver, colon, brain, kidney and skeletal sarcomas. At the proteomic level, we find that the expression of AST is associated with distinct pan-cancer molecular subtypes with an enrichment of specific metabolic and immune signatures. Based on human protein-protein interaction data, AST physically interacts with multiple proteins involved in tumor initiation, suppression, progression, and treatment. We find enrichments in the AST interactomes for proteins associated with liver and lung cancer and dermatologic diseases. At the regulatory level, the GOT1 interactome is enriched with the targets of cancer-associated miRNAs, specifically mir34a - a promising cancer therapeutic, while the GOT2 interactome is enriched with proteins that interact with cancer-associated transcription factors. Conclusions Our findings suggest that perturbations in the levels of AST within specific tissues reflect pathophysiological changes beyond tissue damage and have implications for cancer metabolism, immune infiltration, prognosis, and treatment personalization.
Collapse
Affiliation(s)
| | - Amit G. Singal
- Department of Learning Health Sciences, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX
- Center for Global Health Equity, University of Michigan, Ann Arbor, MI, USA
| | - Akbar K. Waljee
- Department of Learning Health Sciences, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX
- Center for Global Health Equity, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|
|
10
|
Li X, Zhang HS. Amino acid metabolism, redox balance and epigenetic regulation in cancer. FEBS J 2024; 291:412-429. [PMID: 37129434 DOI: 10.1111/febs.16803] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 04/11/2023] [Accepted: 04/21/2023] [Indexed: 05/03/2023]
Abstract
Amino acids act as versatile nutrients driving cell growth and survival, especially in cancer cells. Amino acid metabolism comprises numerous metabolic networks and is closely linked with intracellular redox balance and epigenetic regulation. Reprogrammed amino acid metabolism has been recognized as a ubiquitous feature in tumour cells. This review outlines the metabolism of several primary amino acids in cancer cells and highlights the pivotal role of amino acid metabolism in sustaining redox homeostasis and regulating epigenetic modification in response to oxidative and genetic stress in cancer cells.
Collapse
Affiliation(s)
- Xiang Li
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Hong-Sheng Zhang
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| |
Collapse
|
|
11
|
Abstract
This commentary highlights the key recent advances made in the field of pancreatic cancer. Although there has yet to be a major breakthrough in clinical care for the majority of patients, significant strides have been made in understanding the complex biology of this malignancy and identifying new therapeutic targets.
Collapse
Affiliation(s)
- Emilie A.K. Warren
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Gregory B. Lesinski
- Department of Hematology & Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Shishir K. Maithel
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
| |
Collapse
|
|
12
|
Ren LL, Mao T, Meng P, Zhang L, Wei HY, Tian ZB. Glutamine addiction and therapeutic strategies in pancreatic cancer. World J Gastrointest Oncol 2023; 15:1852-1863. [PMID: 38077649 PMCID: PMC10701242 DOI: 10.4251/wjgo.v15.i11.1852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 09/06/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis, early metastasis, and poor prognosis. Because current therapeutic options are limited, there is an urgent need to investigate novel targeted treatment strategies. Pancreatic cancer faces significant metabolic challenges, principally hypoxia and nutrient deprivation, due to specific microenvironmental constraints, including an extensive desmoplastic stromal reaction. Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation. Increased glucose uptake and glycolytic pathway activity during this process have been extensively described. However, growing evidence suggests that pancreatic cancer cells are glutamine addicted. As a nitrogen source, glutamine directly (or indirectly via glutamate conversion) contributes to many anabolic processes in pancreatic cancer, including amino acids, nucleobases, and hexosamine biosynthesis. It also plays an important role in redox homeostasis, and when converted to α-ketoglutarate, glutamine serves as an energy and anaplerotic carbon source, replenishing the tricarboxylic acid cycle intermediates. The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer, focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.
Collapse
Affiliation(s)
- Lin-Lin Ren
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Pin Meng
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Li Zhang
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Hong-Yun Wei
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Zi-Bin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| |
Collapse
|
|
13
|
Alberghina L. The Warburg Effect Explained: Integration of Enhanced Glycolysis with Heterogeneous Mitochondria to Promote Cancer Cell Proliferation. Int J Mol Sci 2023; 24:15787. [PMID: 37958775 PMCID: PMC10648413 DOI: 10.3390/ijms242115787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
The Warburg effect is the long-standing riddle of cancer biology. How does aerobic glycolysis, inefficient in producing ATP, confer a growth advantage to cancer cells? A new evaluation of a large set of literature findings covering the Warburg effect and its yeast counterpart, the Crabtree effect, led to an innovative working hypothesis presented here. It holds that enhanced glycolysis partially inactivates oxidative phosphorylation to induce functional rewiring of a set of TCA cycle enzymes to generate new non-canonical metabolic pathways that sustain faster growth rates. The hypothesis has been structured by constructing two metabolic maps, one for cancer metabolism and the other for the yeast Crabtree effect. New lines of investigation, suggested by these maps, are discussed as instrumental in leading toward a better understanding of cancer biology in order to allow the development of more efficient metabolism-targeted anticancer drugs.
Collapse
Affiliation(s)
- Lilia Alberghina
- Centre of Systems Biology, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy
| |
Collapse
|
|
14
|
Barar E, Shi J. Genome, Metabolism, or Immunity: Which Is the Primary Decider of Pancreatic Cancer Fate through Non-Apoptotic Cell Death? Biomedicines 2023; 11:2792. [PMID: 37893166 PMCID: PMC10603981 DOI: 10.3390/biomedicines11102792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a solid tumor characterized by poor prognosis and resistance to treatment. Resistance to apoptosis, a cell death process, and anti-apoptotic mechanisms, are some of the hallmarks of cancer. Exploring non-apoptotic cell death mechanisms provides an opportunity to overcome apoptosis resistance in PDAC. Several recent studies evaluated ferroptosis, necroptosis, and pyroptosis as the non-apoptotic cell death processes in PDAC that play a crucial role in the prognosis and treatment of this disease. Ferroptosis, necroptosis, and pyroptosis play a crucial role in PDAC development via several signaling pathways, gene expression, and immunity regulation. This review summarizes the current understanding of how ferroptosis, necroptosis, and pyroptosis interact with signaling pathways, the genome, the immune system, the metabolism, and other factors in the prognosis and treatment of PDAC.
Collapse
Affiliation(s)
- Erfaneh Barar
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran 1416753955, Iran
| | - Jiaqi Shi
- Department of Pathology & Clinical Labs, Rogel Cancer Center, Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI 48109, USA
| |
Collapse
|
|
15
|
Zhang X, Chen J, Xi B, Liu Y, Wang S, Gu L, Zhao H, Tao L, Hua Y, Wang Y, Chen M. Agrimoniin is a dual inhibitor of AKT and ERK pathways that inhibit pancreatic cancer cell proliferation. Phytother Res 2023; 37:4076-4091. [PMID: 37156642 DOI: 10.1002/ptr.7867] [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: 01/08/2023] [Revised: 04/08/2023] [Accepted: 04/25/2023] [Indexed: 05/10/2023]
Abstract
Molecular-targeted therapy has shown its effectiveness in pancreatic cancer, while single-targeted drug often cannot provide long-term benefit because of drug resistance. Fortunately, multitarget combination therapy can reverse drug resistance and achieve better efficacy. The typical treatment characteristics of traditional Chinese medicine monomer on tumor are multiple targets, with small side effects, low toxicity, and so forth. Agrimoniin has been reported to be effective on some cancers, while the mechanism still needs to be clarified. In this study, we used 5-ethynyl-2'-deoxyuridine, cell counting kit-8, flow cytometry, and western blot experiments to confirm that agrimoniin can significantly inhibit the proliferation of pancreatic cancer cell PANC-1 by inducing apoptosis and cell cycle arrest. In addition, by using SC79, LY294002 (the agonist or inhibitor of AKT pathway), and U0126 (the inhibitor of ERK pathway), we found that agrimoniin inhibited cell proliferation by simultaneously inhibiting AKT and ERK pathways. Moreover, agrimoniin could significantly increase the inhibitory effect of LY294002 and U0126 on pancreatic cancer cells. Meanwhile, in vivo experiments also supported the above results. In general, agrimoniin is a double-target inhibitor of AKT and ERK pathways in pancreatic cancer cells; it is expected to be used as a resistance reversal agent of targeted drugs or a synergistic drug of the inhibitor of AKT pathway or ERK pathway.
Collapse
Affiliation(s)
- Xiongfei Zhang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jianping Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Beili Xi
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yutong Liu
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shaojun Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ling Gu
- College of Traditional Chinese Medicine & Integrated Chinese and Western Medicine College, Nanjing University of Chinese Medicine, Nanjing, China
| | - Huanhuan Zhao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Li Tao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Hua
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Wang
- Endoscopy Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Meijuan Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| |
Collapse
|
|
16
|
Dalmasso B, Ghiorzo P. Long Non-Coding RNAs and Metabolic Rewiring in Pancreatic Cancer. Cancers (Basel) 2023; 15:3486. [PMID: 37444595 PMCID: PMC10340399 DOI: 10.3390/cancers15133486] [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: 06/05/2023] [Revised: 06/23/2023] [Accepted: 06/29/2023] [Indexed: 07/15/2023] Open
Abstract
Pancreatic adenocarcinoma is a highly aggressive disease with a poor prognosis. The reprogramming of energetic metabolism has long been implicated in pancreatic tumorigenesis and/or resistance to treatment. Considering that long non-coding RNA dysregulation has been described both in cancerogenesis and in the altered homeostasis of several metabolic pathways, metabolism-associated lncRNAs can contribute to pancreatic cancer evolution. The objective of this review is to assess the burden of lncRNA dysregulation in pancreatic cancer metabolic reprogramming, and its effect on this tumor's natural course and response to treatment. Therefore, we reviewed the available literature to assess whether metabolism-associated lncRNAs have been found to be differentially expressed in pancreatic cancer, as well as whether experimental evidence of their role in such pathways can be demonstrated. Specifically, we provide a comprehensive overview of lncRNAs that are implicated in hypoxia-related pathways, as well as in the reprogramming of autophagy, lipid metabolism, and amino acid metabolism. Our review gathers background material for further research on possible applications of metabolism-associated lncRNAs as diagnostic/prognostic biomarkers and/or as potential therapeutic targets in pancreatic adenocarcinoma.
Collapse
Affiliation(s)
- Bruna Dalmasso
- IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy;
| | - Paola Ghiorzo
- IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy;
- Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy
| |
Collapse
|
|
17
|
MicroRNA-377: A therapeutic and diagnostic tumor marker. Int J Biol Macromol 2023; 226:1226-1235. [PMID: 36442575 DOI: 10.1016/j.ijbiomac.2022.11.236] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/15/2022] [Accepted: 11/18/2022] [Indexed: 11/26/2022]
Abstract
Cancer is considered as one of the main causes of human deaths globally. Despite the recent progresses in therapeutic modalities, there is still a high rate of mortality among cancer patients. Late diagnosis in advanced tumor stages is one of the main reasons for treatment failure in cancer patients. Therefore, it is required to suggest the novel strategies for the early tumor detection. MicroRNAs (miRNAs) have critical roles in neoplastic transformation by regulation of cell proliferation, migration, and apoptosis. They are always considered as non-invasive markers due to their high stability in body fluids. Since, all of the miRNAs have tissue-specific functions in different tumors as tumor suppressor or oncogene; it is required to investigate the molecular mechanisms of every miRNA in different tumors to introduce that as a suitable non-invasive diagnostic marker in cancer patients. For the first time in the present review, we discussed the role of miR-377 during tumor progression. It has been reported that miR-377 mainly functions as a tumor suppressor through the regulation of signaling pathways and transcription factors. This review is an important step toward introducing the miR-377 as a novel diagnostic marker as well as a therapeutic target in cancer patients.
Collapse
|
|
18
|
Li W, Fu H, Fang L, Chai H, Gao T, Chen Z, Qian S. Shikonin induces ferroptosis in multiple myeloma via GOT1-mediated ferritinophagy. Front Oncol 2022; 12:1025067. [PMID: 36387145 PMCID: PMC9641271 DOI: 10.3389/fonc.2022.1025067] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/07/2022] [Indexed: 10/04/2023] Open
Abstract
Multiple myeloma (MM) is an incurable hematological malignancy that lacks effective therapeutic interventions. Ferroptosis is a newly discovered form of cell death that has shown great potential for MM therapy. As a proteasome inhibitor and necroptosis inducer, shikonin (SHK) performs dual functions in MM cells. However, whether SHK inhibits the development of MM via ferroptosis or any other mechanism remains elusive. Here, we provide evidence that SHK treatment was capable of inducing ferroptosis and immunogenic cell death (ICD) in MM. The results showed that SHK treatment induced lactate dehydrogenase release, triggered cell death, evoked oxidative stress, and enhanced ferrous iron and lipid peroxidation levels. Furthermore, treatment with ferroptosis inhibitors reversed SHK-induced cell death, which indicated that ferroptosis contributed to this phenomenon. Meanwhile, ferroptosis was accompanied by the extracellular release of Adenosine 5'-triphosphate (ATP) and High mobility group protein B1 (HMGB1), which are characteristics of ICD. Further investigation showed that glutamic-oxaloacetic transaminase 1 (GOT1) acted as a critical mediator of SHK-induced ferroptosis by promoting ferritinophagy. In conclusion, our findings suggest that SHK exerts ferroptotic effects on MM by regulating GOT1-mediated ferritinophagy. Thus, SHK is a potential therapeutic agent for MM.
Collapse
Affiliation(s)
- Wenxia Li
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Hematology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hangjie Fu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Liuyuan Fang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Hematology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hui Chai
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Tianwen Gao
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhenzhen Chen
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Hematology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shenxian Qian
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- Department of Hematology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
19
|
The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay. Bioorg Med Chem Lett 2022; 73:128883. [PMID: 35820623 DOI: 10.1016/j.bmcl.2022.128883] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/08/2022] [Accepted: 07/05/2022] [Indexed: 11/20/2022]
Abstract
Glutamate oxaloacetate transaminase 1 (GOT1) plays a key role in aberrant glutamine metabolism. GOT1 suppression can arrest tumor growth and prevent the development of cancer, indicating GOT1 as a potential anticancer target. Reported GOT1 inhibitors, on the other hand, are quite restricted. Here, we developed and optimized a coupling reaction-based high-throughput screening assay for the discovery of GOT1 inhibitors. By using this screening assay, we found that the cardiovascular drug hydralazine hydrochloride inhibited GOT1 catalytic activity, with an IC50 of 26.62 ± 7.45 μM, in a non-competitive and partial-reversible manner. In addition, we determined the binding affinity of hydralazine hydrochloride to GOT1, with a Kd of 16.54 ± 8.59 μM, using a microscale thermophoresis assay. According to structure-activity relationship analysis, the inhibitory activity of hydralazine hydrochloride is mainly derived from its hydrazine group. Furthermore, it inhibits the proliferation of cancer cells MCF-7 and MDA-MB-468 with a slight inhibitory effect compared to other tested cancer cells, highlighting GOT1 as a promising therapeutic target for the treatment of breast cancer.
Collapse
|
|
20
|
Long Noncoding RNAs and Circular RNAs in the Metabolic Reprogramming of Lung Cancer: Functions, Mechanisms, and Clinical Potential. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4802338. [PMID: 35757505 PMCID: PMC9217624 DOI: 10.1155/2022/4802338] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/25/2021] [Accepted: 05/12/2022] [Indexed: 11/18/2022]
Abstract
As key regulators of gene function, long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are generally accepted to be involved in lung cancer pathogenesis and progression. Recent research has clarified the phenomenon of metabolic reprogramming in lung cancer because of its significant role in tumor proliferation, migration, invasion, metastasis, and other malignant biological behaviors. Emerging evidence has also shown a relationship between the aberrant expression of lncRNAs and circRNAs and metabolic reprogramming in lung cancer tumorigenesis. This review provides insight regarding the roles of different lncRNAs and circRNAs in lung cancer metabolic reprogramming, by how they target transporter proteins and key enzymes in glucose, lipid, and glutamine metabolic signaling pathways. The clinical potential of lncRNAs and circRNAs as early diagnostic biomarkers and components of therapeutic strategies in lung cancer is further discussed, including current challenges in their utilization from the bench to the bedside and how to adopt a proper delivery system for their therapeutic use.
Collapse
|
|
21
|
Oberkersch RE, Pontarin G, Astone M, Spizzotin M, Arslanbaeva L, Tosi G, Panieri E, Ricciardi S, Allega MF, Brossa A, Grumati P, Bussolati B, Biffo S, Tardito S, Santoro MM. Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis. Dev Cell 2022; 57:1241-1256.e8. [PMID: 35580611 DOI: 10.1016/j.devcel.2022.04.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/24/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022]
Abstract
Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive. We here shown in both human cell lines and mouse models that during developmental and pathological angiogenesis, endothelial cells (ECs) use glutaminolysis-derived glutamate to produce aspartate (Asp) via aspartate aminotransferase (AST/GOT). Asp leads to mTORC1 activation which, in turn, regulates endothelial translation machinery for VEGFR2 and FGFR1 synthesis. Asp-dependent mTORC1 pathway activation also regulates de novo pyrimidine synthesis in angiogenic ECs. These findings identify glutaminolysis-derived Asp as a regulator of mTORC1-dependent endothelial translation and pyrimidine synthesis. Our studies may help overcome anti-VEGF therapy resistance by targeting endothelial growth factor receptor translation.
Collapse
Affiliation(s)
- Roxana E Oberkersch
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Giovanna Pontarin
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Matteo Astone
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Marianna Spizzotin
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Liaisan Arslanbaeva
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Giovanni Tosi
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy
| | - Emiliano Panieri
- Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Sara Ricciardi
- National Institute of Molecular Genetics (INGM) and Department of Biosciences, University of Milan, Milan, Italy
| | - Maria Francesca Allega
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G611QH, UK
| | - Alessia Brossa
- Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Paolo Grumati
- Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy
| | | | - Stefano Biffo
- National Institute of Molecular Genetics (INGM) and Department of Biosciences, University of Milan, Milan, Italy
| | - Saverio Tardito
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G611BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G611QH, UK
| | - Massimo M Santoro
- Laboratory of Angiogenesis and Redox Metabolism, Department of Biology, University of Padua, Padua, Italy.
| |
Collapse
|
|
22
|
Song Z, Yang Y, Wu Y, Zheng M, Sun D, Li H, Chen L. Glutamic oxaloacetic transaminase 1 as a potential target in human cancer. Eur J Pharmacol 2022; 917:174754. [PMID: 35007521 DOI: 10.1016/j.ejphar.2022.174754] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/08/2021] [Accepted: 01/06/2022] [Indexed: 12/31/2022]
Abstract
Glutamic Oxaloacetic Transaminase 1 (GOT1) is one distinct isoenzyme of glutamic oxaloacetic transaminase in eukaryotic cells, which is located in the cytoplasm. To date, several studies have shown that GOT1 plays a critical role in regulating cell proliferation by participating in amino acid metabolism, especially in glutamine metabolism. In addition, GOT1 is overexpressed in many cancer, so GOT1 has been identified as a potentially therapeutic target. Herein, this review summarizes the structure and function of GOT1 and the important roles of GOT1 in some tumor progress, as well as the characterization of GOT1 inhibitors. It may provide new insight into the discovery of small compounds as potential anti-GOT1 drugs for treatment of cancer.
Collapse
Affiliation(s)
- Zhuorui Song
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yueying Yang
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yanli Wu
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mengzhu Zheng
- Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| |
Collapse
|
|
23
|
Halama A, Suhre K. Advancing Cancer Treatment by Targeting Glutamine Metabolism-A Roadmap. Cancers (Basel) 2022; 14:553. [PMID: 35158820 PMCID: PMC8833671 DOI: 10.3390/cancers14030553] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.
Collapse
Affiliation(s)
- Anna Halama
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha 24144, Qatar
| | - Karsten Suhre
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha 24144, Qatar
| |
Collapse
|
|
24
|
Smalling RV, Bechard ME, Duryea J, Kingsley PJ, Roberts ER, Marnett LJ, Bilbao D, Stauffer SR, McDonald OG. Aminopyridine analogs selectively target metastatic pancreatic cancer. Oncogene 2022; 41:1518-1525. [PMID: 35031771 DOI: 10.1038/s41388-022-02183-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/17/2021] [Accepted: 01/07/2022] [Indexed: 12/20/2022]
Abstract
Metastatic outgrowth is supported by metabolic adaptations that may differ from the primary tumor of origin. However, it is unknown if such adaptations are therapeutically actionable. Here we report a novel aminopyridine compound that targets a unique Phosphogluconate Dehydrogenase (PGD)-dependent metabolic adaptation in distant metastases from pancreatic cancer patients. Compared to structurally similar analogs, 6-aminopicolamine (6AP) potently and selectively reversed PGD-dependent metastatic properties, including intrinsic tumorigenic capacity, excess glucose consumption, and global histone hyperacetylation. 6AP acted as a water-soluble prodrug that was converted into intracellular bioactive metabolites that inhibited PGD in vitro, and 6AP monotherapy demonstrated anti-metastatic efficacy with minimal toxicity in vivo. Collectively, these studies identify 6AP and possibly other 6-aminopyridines as well-tolerated prodrugs with selectivity for metastatic pancreatic cancers. If unique metabolic adaptations are a common feature of metastatic or otherwise aggressive human malignancies, then such dependencies could provide a largely untapped pool of druggable targets for patients with advanced cancers.
Collapse
Affiliation(s)
- Rana V Smalling
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Matthew E Bechard
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jeff Duryea
- Department of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Philip J Kingsley
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Evan R Roberts
- Department of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Lawrence J Marnett
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Daniel Bilbao
- Department of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Shaun R Stauffer
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.,Center for Therapeutics Discovery, Cleveland Clinic, Cleveland, OH, USA
| | - Oliver G McDonald
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. .,Department of Pathology and Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
| |
Collapse
|
|
25
|
Zhou S, Guo Z, Lv X, Zhang X. CircGOT1 promotes cell proliferation, mobility, and glycolysis-mediated cisplatin resistance via inhibiting its host gene GOT1 in esophageal squamous cell cancer. Cell Cycle 2021; 21:247-260. [PMID: 34919012 DOI: 10.1080/15384101.2021.2015671] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Esophageal squamous cell cancer (ESCC) is a prevalent malignant cancer with high incidence and fatality rate. Surging evidences have revealed that circular RNAs (circRNAs) act key role in ESCC tumorigenesis and progression. Therefore, the purpose of this study is to explore the role and regulatory mechanism of a novel circGOT1 in ESCC. In the present study, the transcriptional expression of circGOT1, miR-606 and GOT1, and the epithelial-mesenchymal transition (EMT) and apoptosis-related markers were examined by quantitative PCR. The protein levels of GOT1 and glycolysis-related proteins were detected by Western blotting. In addition, the glycolytic levels were determined via measuring glucose uptake, lactate production, and ATP levels. Then, the function experiments and rescue experiments were used to investigate the function and mechanism of circGOT1 in ESCC. In addition, RNA immunoprecipitation, pull-down, and luciferase activity reporter gene assays were used to analyze the circGOT1/miR-606/GOT1 axis. The xenograft mouse mode was used to determine the function of circGOT1 in vivo. Here, we identified that circGOT1 and GOT1 upregulate, whereas miR-606 was reduced in ESCC tissues and cell lines. High circGOT1 and GOT1 expression associated with poor survival and worse prognosis of ESCC patients, but miR-606 revealed opposite traits. Mechanically, circGOT1 sponged miR-606 to promote GOT1, which induced cell proliferation, migration, aerobic glycolysis, and cisplatin resistance. The tumor growth was reduced by circGOT1 inhibition in xenograft mouse. Our results indicate the oncogene role of circGOT1 in ESCC via an endogenous competition RNA (ceRNA) mechanism to promote GOT1 expression via sponging miR-606.
Collapse
Affiliation(s)
- Shasha Zhou
- Department of Oncology, Hebei Medical University, Shijiazhuang, P.R. China.,Department of Oncology, Handan Central Hospital, Handan, P.R. China
| | - Zhiyuan Guo
- Department of Oncology, Handan Central Hospital, Handan, P.R. China
| | - Xueli Lv
- Department of Oncology, Shexian Hospital, Shexian, P.R. China
| | - Xueqiang Zhang
- Department of Oncology, Hebei Medical University, Shijiazhuang, P.R. China.,Department of Oncology, Handan Central Hospital, Handan, P.R. China
| |
Collapse
|
|
26
|
Opportunities and challenges in targeted therapy and immunotherapy for pancreatic cancer. Expert Rev Mol Med 2021; 23:e21. [PMID: 34906271 DOI: 10.1017/erm.2021.26] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer is one of the most malignant tumours with a poor prognosis. In recent years, the incidence of pancreatic cancer is on the rise. Traditional chemotherapy and radiotherapy for pancreatic cancer have been improved, first-line and second-line palliative treatments have been developed, and adjuvant treatments have also been used in clinical. However, the 5-year survival rate is still less than 10% and new treatment methods such as targeted therapy and immunotherapy need to be investigated. In the past decades, many clinical trials of targeted therapies and immunotherapies for pancreatic cancer were launched and some of them showed an ideal prospect in a subgroup of pancreatic cancer patients. The experience of both success and failure of these clinical trials will be helpful to improve these therapies in the future. Therefore, the current research progress and challenges of selected targeted therapies and immunotherapies for pancreatic cancer are reviewed.
Collapse
|
|
27
|
Maryška M, Svobodová L, Dehaen W, Hrabinová M, Rumlová M, Soukup O, Kuchař M. Heterocyclic Cathinones as Inhibitors of Kynurenine Aminotransferase II-Design, Synthesis, and Evaluation. Pharmaceuticals (Basel) 2021; 14:ph14121291. [PMID: 34959692 PMCID: PMC8708382 DOI: 10.3390/ph14121291] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/24/2021] [Accepted: 12/08/2021] [Indexed: 11/16/2022] Open
Abstract
Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM.
Collapse
Affiliation(s)
- Michal Maryška
- Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 5, 16628 Prague, Czech Republic; (M.M.); (L.S.)
- National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic
| | - Lucie Svobodová
- Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 5, 16628 Prague, Czech Republic; (M.M.); (L.S.)
| | - Wim Dehaen
- CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technická 5, 16628 Prague, Czech Republic;
| | - Martina Hrabinová
- Biomedical Research Center, University Hospital Hradec Králové, Sokolská 581, 50005 Hradec Kralové, Czech Republic; (M.H.); (O.S.)
- Department of Toxicology and Military Pharmacy, University of Defense, Třebešská 1575, 50005 Hradec Králové, Czech Republic
| | - Michaela Rumlová
- Department of Biotechnology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 5, 16628 Prague, Czech Republic;
| | - Ondřej Soukup
- Biomedical Research Center, University Hospital Hradec Králové, Sokolská 581, 50005 Hradec Kralové, Czech Republic; (M.H.); (O.S.)
- Department of Toxicology and Military Pharmacy, University of Defense, Třebešská 1575, 50005 Hradec Králové, Czech Republic
| | - Martin Kuchař
- Forensic Laboratory of Biologically Active Substances, Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology, University of Chemistry and Technology Prague, Technická 5, 16628 Prague, Czech Republic; (M.M.); (L.S.)
- National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic
- Correspondence: ; Tel.: +420-220-444-431
| |
Collapse
|
|
28
|
DeLiberty JM, Robb R, Gates CE, Bryant KL. Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain. Adv Cancer Res 2021; 153:267-304. [PMID: 35101233 DOI: 10.1016/bs.acr.2021.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function. This unique metabolic landscape promotes tumorigenesis, proliferation, survival in nutrient deficient environments and confers resistance to conventional cytotoxic and targeted therapies. Emerging work demonstrates how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials. This review aims to outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention.
Collapse
Affiliation(s)
- Jonathan M DeLiberty
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ryan Robb
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Claire E Gates
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kirsten L Bryant
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
| |
Collapse
|
|
29
|
GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis. Nat Commun 2021; 12:4860. [PMID: 34381026 PMCID: PMC8357841 DOI: 10.1038/s41467-021-24859-2] [Citation(s) in RCA: 164] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/08/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer metabolism is rewired to support cell survival in response to intrinsic and environmental stressors. Identification of strategies to target these adaptions is an area of active research. We previously described a cytosolic aspartate aminotransaminase (GOT1)-driven pathway in pancreatic cancer used to maintain redox balance. Here, we sought to identify metabolic dependencies following GOT1 inhibition to exploit this feature of pancreatic cancer and to provide additional insight into regulation of redox metabolism. Using pharmacological methods, we identify cysteine, glutathione, and lipid antioxidant function as metabolic vulnerabilities following GOT1 withdrawal. We demonstrate that targeting any of these pathways triggers ferroptosis, an oxidative, iron-dependent form of cell death, in GOT1 knockdown cells. Mechanistically, we reveal that GOT1 inhibition represses mitochondrial metabolism and promotes a catabolic state. Consequently, we find that this enhances labile iron availability through autophagy, which potentiates the activity of ferroptotic stimuli. Overall, our study identifies a biochemical connection between GOT1, iron regulation, and ferroptosis.
Collapse
|
|
30
|
Structural and functional analysis of disease-associated mutations in GOT1 gene: An in silico study. Comput Biol Med 2021; 136:104695. [PMID: 34352456 DOI: 10.1016/j.compbiomed.2021.104695] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 07/23/2021] [Indexed: 11/20/2022]
Abstract
Disease-associated single nucleotide polymorphisms (SNPs) alter the natural functioning and the structure of proteins. Glutamic-oxaloacetic transaminase 1 (GOT1) is a gene associated with multiple cancers and neurodegenerative diseases which codes for aspartate aminotransferase. The present study involved a comprehensive in-silico analysis of the disease-associated SNPs of human GOT1. Four highly deleterious nsSNPs (L36R, Y159C, W162C and L345P) were identified through SNP screening using several sequence-based and structure-based tools. Conservation analysis and oncogenic analysis showed that most of the nsSNPs are at highly conserved residues, oncogenic in nature and cancer drivers. Molecular dynamics simulations (MDS) analysis was performed to understand the dynamic behaviour of native and mutant proteins. PTM analysis revealed that the nsSNP Y159C is at a PTM site and will mostly affect phosphorylation at that site. Based on the overall analyses carried out in this study, L36R is the most deleterious mutation amongst the aforementioned deleterious mutations of GOT1.
Collapse
|
|
31
|
Jain P, Dvorkin-Gheva A, Mollen E, Malbeteau L, Xie M, Jessa F, Dhavarasa P, Chung S, Brown KR, Jang GH, Vora P, Notta F, Moffat J, Hedley D, Boutros PC, Wouters BG, Koritzinsky M. NOX4 links metabolic regulation in pancreatic cancer to endoplasmic reticulum redox vulnerability and dependence on PRDX4. SCIENCE ADVANCES 2021; 7:7/19/eabf7114. [PMID: 33962950 PMCID: PMC8104867 DOI: 10.1126/sciadv.abf7114] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/18/2021] [Indexed: 05/02/2023]
Abstract
There is an urgent need to identify vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). PDAC cells acquire metabolic changes that augment NADPH production and cytosolic redox homeostasis. Here, we show that high NADPH levels drive activity of NADPH oxidase 4 (NOX4) expressed in the endoplasmic reticulum (ER) membrane. NOX4 produces H2O2 metabolized by peroxiredoxin 4 (PRDX4) in the ER lumen. Using functional genomics and subsequent in vitro and in vivo validations, we find that PDAC cell lines with high NADPH levels are dependent on PRDX4 for their growth and survival. PRDX4 addiction is associated with increased reactive oxygen species, a DNA-PKcs-governed DNA damage response and radiosensitivity, which can be rescued by depletion of NOX4 or NADPH. Hence, this study has identified NOX4 as a protein that paradoxically converts the reducing power of the cytosol to an ER-specific oxidative stress vulnerability in PDAC that may be therapeutically exploited by targeting PRDX4.
Collapse
Affiliation(s)
- Pallavi Jain
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Anna Dvorkin-Gheva
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Erik Mollen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- University of Maastricht, Maastricht, Netherlands
| | - Lucie Malbeteau
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Michael Xie
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Fatima Jessa
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Piriththiv Dhavarasa
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Stephen Chung
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Kevin R Brown
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Ontario, Canada
| | - Gun Ho Jang
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Parth Vora
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Faiyaz Notta
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Jason Moffat
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - David Hedley
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Paul C Boutros
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Departments of Human Genetics and Urology, University of California, Los Angeles, Los Angeles, CA, USA
| | - Bradly G Wouters
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| | - Marianne Koritzinsky
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
32
|
Dopico-López A, Pérez-Mato M, da Silva-Candal A, Iglesias-Rey R, Rabinkov A, Bugallo-Casal A, Sobrino T, Mirelman D, Castillo J, Campos F. Inhibition of endogenous blood glutamate oxaloacetate transaminase enhances the ischemic damage. Transl Res 2021; 230:68-81. [PMID: 33132087 DOI: 10.1016/j.trsl.2020.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/22/2020] [Accepted: 10/19/2020] [Indexed: 12/01/2022]
Abstract
Glutamate oxaloacetate transaminase 1 (GOT1) enzyme plays a critical role in the cell metabolism by participating in the carbohydrate and amino acid metabolism. In ischemic stroke, we have demonstrated that recombinant GOT1 acts as a novel neuroprotective treatment against the excess of extracellular glutamate that accumulates in the brain following ischemic stroke. In this study, we investigated the inhibitory effect of GOT1 on brain metabolism and on the ischemic damage in a rat model of ischemic stroke by means of a specific antibody developed against this enzyme. Inhibition of GOT1 caused higher brain glutamate and lactate levels and this response was associated with larger ischemic lesion. This study represents the first demonstration that the inhibition of the blood GOT1 activity leads to more severe ischemic damage and poorer outcome and supports the protective role of GOT1 against ischemic insults.
Collapse
Affiliation(s)
- Antonio Dopico-López
- Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - María Pérez-Mato
- Neuroscience and Cerebrovascular Research Laboratory, Department of Neurology and Stroke Center, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Universidad Autónoma de Madrid, Madrid, Spain.
| | - Andrés da Silva-Candal
- Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Ramón Iglesias-Rey
- Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Aharon Rabinkov
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Ana Bugallo-Casal
- Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Tomás Sobrino
- Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - David Mirelman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - José Castillo
- Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Francisco Campos
- Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
| |
Collapse
|
|
33
|
Noorbakhsh A, Hosseininezhadian Koushki E, Farshadfar C, Ardalan N. Designing a natural inhibitor against human kynurenine aminotransferase type II and a comparison with PF-04859989: a computational effort against schizophrenia. J Biomol Struct Dyn 2021; 40:7038-7051. [PMID: 33645449 DOI: 10.1080/07391102.2021.1893817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The Kynurenine aminotransferase II (KATII) enzyme has an essential role in L-kynurenine transmission to kynurenic acid (KYNA). High concentration of kynurenic acid associates with schizophrenia and some neurocognitive disorders. Decreasing KYNA production via inhibiting KATII would be an effective method for treating and understanding the related central nervous system (CNS) diseases. This study aimed to discover a potent inhibitor against human KATII (hKATII) in comparison with PF-04859989. We utilized the computational methods of molecular dynamics, virtual screening, docking, and binding free-energy calculations. Initially, the 58722 compounds from three drug libraries, including IBS library, DrugBank library, and Analyticon library, were obtained. At the next stage, these sets of compounds were screened by AutoDock Vina software, and a potent inhibitor (ZINC35466084) was selected. Following the screening, molecular dynamics simulations for both ZINC35466084 and PF-04859989 were performed by GROMACS software. MM-PBSA analysis showed that the amount of binding free energy for ZINC35466084 (-61.26 KJ mol-1) is more potent than PF-04859989 (-43.14 KJ mol-1). Furthermore, the ADME analysis results revealed that the pharmacokinetic parameters of ZINC35466084 are acceptable for human use. Eventually, our data demonstrated that ZINC35466084 is suitable for hKATII inhibition, and it is an appropriate candidate for further studies in the laboratory. Communicated by Ramaswamy H. Sarma.
Collapse
Affiliation(s)
- Akbar Noorbakhsh
- Department of Biochemistry, Science and Research Branch, Islamic Azad University, Sanandaj, Iran
| | - Elnaz Hosseininezhadian Koushki
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Chiako Farshadfar
- Department of Biochemistry, Science and Research Branch, Islamic Azad University, Sanandaj, Iran
| | - Noeman Ardalan
- Department of Microbiology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| |
Collapse
|
|
34
|
Zhu X, Han J, Lan H, Lin Q, Wang Y, Sun X. A novel circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 pathway regulates cisplatin-resistance in non-small cell lung cancer (NSCLC). BMC Cancer 2020; 20:1190. [PMID: 33276753 PMCID: PMC7716498 DOI: 10.1186/s12885-020-07680-w] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/23/2020] [Indexed: 12/22/2022] Open
Abstract
Background Cisplatin is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and emerging evidences suggests that targeting circular RNAs (circRNAs) is an effective strategy to increase cisplatin-sensitivity in NSCLC, but the detailed mechanisms are still not fully delineated. Methods Cell proliferation, viability and apoptosis were examined by using the cell counting kit-8 (CCK-8) assay, trypan blue staining assay and Annexin V-FITC/PI double staining assay, respectively. The expression levels of cancer associated genes were measured by using the Real-Time qPCR and Western Blot analysis at transcriptional and translated levels. Dual-luciferase reporter gene system assay was conducted to validated the targeting sites among hsa_circRNA_103809, miR-377-3p and 3′ untranslated region (3’UTR) of GOT1 mRNA. The expression status, including expression levels and localization, were determined by immunohistochemistry (IHC) assay in mice tumor tissues. Results Here we identified a novel hsa_circRNA_103809/miR-377-3p/GOT1 signaling cascade which contributes to cisplatin-resistance in NSCLC in vitro and in vivo. Mechanistically, parental cisplatin-sensitive NSCLC (CS-NSCLC) cells were subjected to continuous low-dose cisplatin treatment to generate cisplatin-resistant NSCLC (CR-NSCLC) cells, and we found that hsa_circRNA_103809 and GOT1 were upregulated, while miR-377-3p was downregulated in CR-NSCLC cells but not in CS-NSCLC cells. In addition, hsa_circRNA_103809 sponged miR-337-3p to upregulate GOT1 in CS-NSCLC cells, and knock-down of hsa_circRNA_103809 enhanced the inhibiting effects of cisplatin on cell proliferation and viability, and induced cell apoptosis in CR-NSCLC cells, which were reversed by downregulating miR-377-3p and overexpressing GOT1. Consistently, overexpression of hsa_circRNA_103809 increased cisplatin-resistance in CS-NSCLC cells by regulating the miR-377-3p/GOT1 axis. Finally, silencing of hsa_circRNA_103809 aggravated the inhibiting effects of cisplatin treatment on NSCLC cell growth in vivo. Conclusions Analysis of data suggested that targeting the hsa_circRNA_103809/miR-377-3p/GOT1 pathway increased susceptibility of CR-NSCLC cells to cisplatin, and this study provided novel targets to improve the therapeutic efficacy of cisplatin for NSCLC treatment in clinic. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07680-w.
Collapse
Affiliation(s)
- Xiang Zhu
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Jing Han
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Huiyin Lan
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Qingren Lin
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Yuezhen Wang
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| | - Xiaojiang Sun
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| |
Collapse
|
|
35
|
Xu R, Yang J, Ren B, Wang H, Yang G, Chen Y, You L, Zhao Y. Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies. Front Oncol 2020; 10:572722. [PMID: 33117704 PMCID: PMC7550743 DOI: 10.3389/fonc.2020.572722] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/31/2020] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies with an extremely poor prognosis. Energy metabolism reprogramming, an emerging hallmark of cancer, has been implicated in the tumorigenesis and development of pancreatic cancer. In addition to well-elaborated enhanced glycolysis, investigating the role of reprogramming of amino acid metabolism has sparked great interests in recent years. The rewiring amino acid metabolism orchestrated by genetic alterations contributes to pancreatic cancer malignant characteristics including cell proliferation, invasion, metastasis, angiogenesis and redox balance. In the unique hypoperfused and nutrient-deficient tumor microenvironment (TME), the interactions between cancer cells and stromal components and salvaging processes including autophagy and macropinocytosis play critical roles in fulfilling the metabolic requirements and supporting growth of PDAC. In this review, we elucidate the recent advances in the amino acid metabolism reprogramming in pancreatic cancer and the mechanisms of amino acid metabolism regulating PDAC progression, which will provide opportunities to develop promising therapeutic strategies.
Collapse
Affiliation(s)
- Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Jinshou Yang
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Huanyu Wang
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Gang Yang
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
36
|
Hipólito A, Nunes SC, Vicente JB, Serpa J. Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer. Molecules 2020; 25:molecules25173984. [PMID: 32882966 PMCID: PMC7504796 DOI: 10.3390/molecules25173984] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 08/26/2020] [Accepted: 08/29/2020] [Indexed: 12/16/2022] Open
Abstract
Metabolic remodeling is a critical skill of malignant cells, allowing their survival and spread. The metabolic dynamics and adaptation capacity of cancer cells allow them to escape from damaging stimuli, including breakage or cross-links in DNA strands and increased reactive oxygen species (ROS) levels, promoting resistance to currently available therapies, such as alkylating or oxidative agents. Therefore, it is essential to understand how metabolic pathways and the corresponding enzymatic systems can impact on tumor behavior. Cysteine aminotransferase (CAT) per se, as well as a component of the CAT: 3-mercaptopyruvate sulfurtransferase (MST) axis, is pivotal for this metabolic rewiring, constituting a central mechanism in amino acid metabolism and fulfilling the metabolic needs of cancer cells, thereby supplying other different pathways. In this review, we explore the current state-of-art on CAT function and its role on cancer cell metabolic rewiring as MST partner, and its relevance in cancer cells' fitness.
Collapse
Affiliation(s)
- Ana Hipólito
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculty of Medical Sciences, University NOVA of Lisbon, Campus dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal; (A.H.); (S.C.N.)
- Institute of Oncology Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - Sofia C. Nunes
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculty of Medical Sciences, University NOVA of Lisbon, Campus dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal; (A.H.); (S.C.N.)
- Institute of Oncology Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
| | - João B. Vicente
- Institute of Technology, Chemistry and Biology António Xavier (ITQB NOVA), Avenida da República (EAN), 2780-157 Oeiras, Portugal
- Correspondence: (J.B.V.); (J.S.)
| | - Jacinta Serpa
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculty of Medical Sciences, University NOVA of Lisbon, Campus dos Mártires da Pátria, 130, 1169-056 Lisbon, Portugal; (A.H.); (S.C.N.)
- Institute of Oncology Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisbon, Portugal
- Correspondence: (J.B.V.); (J.S.)
| |
Collapse
|
|
37
|
Oncology Therapeutics Targeting the Metabolism of Amino Acids. Cells 2020; 9:cells9081904. [PMID: 32824193 PMCID: PMC7463463 DOI: 10.3390/cells9081904] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 08/12/2020] [Accepted: 08/13/2020] [Indexed: 12/19/2022] Open
Abstract
Amino acid metabolism promotes cancer cell proliferation and survival by supporting building block synthesis, producing reducing agents to mitigate oxidative stress, and generating immunosuppressive metabolites for immune evasion. Malignant cells rewire amino acid metabolism to maximize their access to nutrients. Amino acid transporter expression is upregulated to acquire amino acids from the extracellular environment. Under nutrient depleted conditions, macropinocytosis can be activated where proteins from the extracellular environment are engulfed and degraded into the constituent amino acids. The demand for non-essential amino acids (NEAAs) can be met through de novo synthesis pathways. Cancer cells can alter various signaling pathways to boost amino acid usage for the generation of nucleotides, reactive oxygen species (ROS) scavenging molecules, and oncometabolites. The importance of amino acid metabolism in cancer proliferation makes it a potential target for therapeutic intervention, including via small molecules and antibodies. In this review, we will delineate the targets related to amino acid metabolism and promising therapeutic approaches.
Collapse
|
|
38
|
Gromisch C, Qadan M, Machado MA, Liu K, Colson Y, Grinstaff MW. Pancreatic Adenocarcinoma: Unconventional Approaches for an Unconventional Disease. Cancer Res 2020; 80:3179-3192. [PMID: 32220831 PMCID: PMC7755309 DOI: 10.1158/0008-5472.can-19-2731] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 02/08/2020] [Accepted: 03/24/2020] [Indexed: 12/16/2022]
Abstract
This review highlights current treatments, limitations, and pitfalls in the management of pancreatic cancer and discusses current research in novel targets and drug development to overcome these clinical challenges. We begin with a review of the clinical landscape of pancreatic cancer, including genetic and environmental risk factors, as well as limitations in disease diagnosis and prevention. We next discuss current treatment paradigms for pancreatic cancer and the shortcomings of targeted therapy in this disease. Targeting major driver mutations in pancreatic cancer, such as dysregulation in the KRAS and TGFβ signaling pathways, have failed to improve survival outcomes compared with nontargeted chemotherapy; thus, we describe new advances in therapy such as Ras-binding pocket inhibitors. We then review next-generation approaches in nanomedicine and drug delivery, focusing on preclinical advancements in novel optical probes, antibodies, small-molecule agents, and nucleic acids to improve surgical outcomes in resectable disease, augment current therapies, expand druggable targets, and minimize morbidity. We conclude by summarizing progress in current research, identifying areas for future exploration in drug development and nanotechnology, and discussing future prospects for management of this disease.
Collapse
Affiliation(s)
- Christopher Gromisch
- Departments of Pharmacology and Experimental Therapeutics, Biomedical Engineering, and Chemistry, Boston University, Boston, Massachusetts
| | - Motaz Qadan
- Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Mariana Albuquerque Machado
- Departments of Pharmacology and Experimental Therapeutics, Biomedical Engineering, and Chemistry, Boston University, Boston, Massachusetts
| | - Kebin Liu
- Department of Biochemistry and Molecular Biology and Georgia Cancer Center, Medical College of Georgia, Augusta, Georgia
| | - Yolonda Colson
- Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts
| | - Mark W Grinstaff
- Departments of Pharmacology and Experimental Therapeutics, Biomedical Engineering, and Chemistry, Boston University, Boston, Massachusetts.
| |
Collapse
|
|
39
|
Divya R, Raj Kumar K. Tadalafil inhibits elevated glutamic oxaloacetic transaminase during alcohol aflatoxin induced hepatocellular carcinoma in rats. ACTA ACUST UNITED AC 2020. [DOI: 10.17352/2455-8591.000022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
|