Abstract
This review presents a comprehensive overview of the role of cuprotosis-associated genes in various cancer types, highlighting their significance in tumor progression and therapy resistance. In breast cancer and colorectal cancer (CRC), dysregulation of genes involved in mitochondrial function and copper metabolism, such as FDX1, LIAS, LIPT1, DLD, DLAT, and PDHA1/PDHB, promotes metabolic reprogramming and enhances cancer cell survival. Ovarian cancer exhibits unique dysregulations in genes like ATP7B, CCS, and COMMD1, influencing copper metabolism and redox signaling pathways, thereby contributing to chemoresistance and tumor growth. Head and neck cancer involves upregulation of MT1X, ATP7A, and CCS, potentially aiding cancer cell survival under oxidative stress conditions. Lung cancer is characterized by distinct dysregulation of genes like SLC31A1, ATOX1, and COMMD1, modulating copper homeostasis and redox signaling to support tumor proliferation. Liver cancer and kidney cancer each present unique sets of dysregulated cuprotosis-associated genes, such as SLC39A4, SCO2, and ATP7A, suggesting novel therapeutic targets specific to these cancer types. Pathway analysis reveals enrichment in mineral absorption pathways, emphasizing the importance of these genes in maintaining cellular mineral homeostasis. Understanding the intricate interplay between cuprotosis-associated genes and cancer biology offers insights into potential therapeutic strategies targeting copper metabolism for improved treatment outcomes across various cancer types.
References
Horgan D, Mia R, Erhabor T, et al., 2022, Fighting Cancer Around the World: A Framework for Action. Healthcare, 10(11): 2125.
Tang R, Xu J, Zhang B, et al., 2020, Ferroptosis, Necroptosis, and Pyroptosis in Anticancer Immunity. Journal of Hematology & Oncology, 13: 1–18.
Yang J, Hu S, Bian Y, et al., 2022, Targeting Cell Death: Pyroptosis, Ferroptosis, Apoptosis and Necroptosis in Osteoarthritis. Frontiers in Cell and Developmental Biology, 9: 789948.
Brady DC, Crowe MS, Turski ML, et al., 2014, Copper is Required for Oncogenic BRAF Signalling and Tumorigenesis. Nature, 509(7501): 492–496.
Yang Z, Feng R, Zhao H, 2024, Cuproptosis and Cu: A New Paradigm in Cellular Death and Their Role in Non-Cancerous Diseases. Apoptosis, 29(9): 1330–1360.
Du J, Huang Z, Li Y, et al., 2023, Copper Exerts Cytotoxicity Through Inhibition of Iron-Sulfur Cluster Biogenesis on ISCA1/ISCA2/ISCU Assembly Proteins. Free Radical Biology and Medicine, 204: 359–373.
Vo TTT, Peng T-Y, Nguyen TH, et al., 2024, The Crosstalk Between Copper-Induced Oxidative Stress and Cuproptosis: A Novel Potential Anticancer Paradigm. Cell Communication and Signaling, 22(1): 353.
Chen J, Jiang Y, Shi H, et al., 2020, The Molecular Mechanisms of Copper Metabolism and Its Roles in Human Diseases. Pflügers Archiv-European Journal of Physiology, 472: 1415–1429.
Chen L, Min J, Wang F, 2022, Copper Homeostasis and Cuproptosis in Health and Disease. Signal Transduction and Targeted Therapy, 7(1): 378.
Shanbhag VC, Gudekar N, Jasmer K, et al., 2021, Copper Metabolism as a Unique Vulnerability in Cancer. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1868(2): 118893.
Zhao R, Sukocheva O, Tse E, et al., 2024, Cuproptosis, the Novel Type of Oxidation-Induced Cell Death in Thoracic Cancers: Can It Enhance the Success of Immunotherapy? Cell Communication and Signaling, 22(1): 379.
Liu WQ, Lin WR, Yan L, et al., 2024, Copper Homeostasis and Cuproptosis in Cancer Immunity and Therapy. Immunological Reviews, 321(1): 211–227.
Ruiz LM, Libedinsky A, Elorza AA, 2021, Role of Copper on Mitochondrial Function and Metabolism. Frontiers in Molecular Biosciences, 8: 711227.
Xue Q, Kang R, Klionsky DJ, et al., 2023, Copper Metabolism in Cell Death and Autophagy. Autophagy, 19(8): 2175–2195.
Lelièvre P, Sancey L, Coll J-L, er al., 2020, The Multifaceted Roles of Copper in Cancer: A Trace Metal Element with Dysregulated Metabolism, but Also a Target or a Bullet for Therapy. Cancers, 12(12): 3594.
Tsvetkov P, Coy S, Petrova B, et al., 2022, Copper Induces Cell Death by Targeting Lipoylated TCA Cycle Proteins. Science, 375(6586): 1254–1261.
Li Y, Qi P, Song S-Y, et al., 2024, Elucidating Cuproptosis in Metabolic Dysfunction-Associated Steatotic Liver Disease. Biomedicine & Pharmacotherapy, 174: 116585.
Lill R, Freibert S-A, 2020, Mechanisms of Mitochondrial Iron-Sulfur Protein Biogenesis. Annual Review of Biochemistry, 89(1): 471–499.
Cronan JE, 2020, Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes. Frontiers in Genetics, 11: 510.
Pavlu-Pereira H, Silva MJ, Florindo C, et al., 2020, Pyruvate Dehydrogenase Complex Deficiency: Updating the Clinical, Metabolic and Mutational Landscapes in a Cohort of Portuguese Patients. Orphanet Journal of Rare Diseases, 15: 1–14.
Huang T, Liu Y, Li J, et al., 2022, Insights Into Prognosis and Immune Infiltration of Cuproptosis-Related Genes in Breast Cancer. Frontiers in Immunology, 13: 1054305.
Dreishpoon MB, Bick NR, Petrova B, et al., 2023, FDX1 Regulates Cellular Protein Lipoylation Through Direct Binding to LIAS. Journal of Biological Chemistry, 299(9): 105046.
Zhao Q, Qi T, 2023, The Implications and Prospect of Cuproptosis-Related Genes and Copper Transporters in Cancer Progression. Frontiers in Oncology, 13: 1117164.
Zhang L, Deng R, Guo R, et al., 2024, Recent Progress of Methods for Cuproptosis Detection. Frontiers in Molecular Biosciences, 11: 1460987.
Echeverri Ruiz NP, Mohan V, Wu J, et al., 2021, Dynamic Regulation of Mitochondrial Pyruvate Metabolism Is Necessary for Orthotopic Pancreatic Tumor Growth. Cancer & Metabolism, 9: 1–12.
Duarte I, Caio J, Moedas M, et al., 2021, Dihydrolipoamide Dehydrogenase, Pyruvate Oxidation, and Acetylation-Dependent Mechanisms Intersecting Drug Iatrogenesis. Cellular and Molecular Life Sciences:1–18.
Zhao H, Li Y, 2021, Cancer Metabolism and Intervention Therapy. Molecular Biomedicine, 2(1): 5.
Shao Y, Fan X, Yang X, et al., 2023, Impact of Cuproptosis-Related Markers on Clinical Status, Tumor Immune Microenvironment, and Immunotherapy in Colorectal Cancer: A Multi-Omic Analysis. Computational and Structural Biotechnology Journal, 21: 3383–403.
Zhang X, Han X, 2024, Targeting Cuproptosis for Cancer Therapy: Focus on the Anti-Tumor Immune System. Cancer Pathogenesis and Therapy, 2: E76.
Crispin A, 2017, HSCB, a Co-Chaperone in Mitochondrial Iron-Sulfur Cluster Biogenesis, Is a Novel Candidate Gene for Congenital Sideroblastic Anemia. Blood, 130(Supplement 1): 79.
Mathias RA, Greco TM, Oberstein A, et al., 2014, Sirtuin 4 Is a Lipoamidase Regulating Pyruvate Dehydrogenase Complex Activity. Cell, 159(7): 1615–1625.
Chen Q, Wang Y, Yang L, et al., 2022, PM2.5 Promotes NSCLC Carcinogenesis Through Translationally and Transcriptionally Activating DLAT-Mediated Glycolysis Reprograming. Journal of Experimental & Clinical Cancer Research, 41(1): 229.
Lazzarino G, O’Halloran P, Di Pietro V, et al., 2022, Pyruvate Dehydrogenase Complex, Metabolic Enzymes, and Energy Derangement in Traumatic Brain Injury. Cellular, Molecular, Physiological, and Behavioral Aspects of Traumatic Brain Injury, Elsevier, Amsterdam, 207–218.
Neitzel C, Demuth P, Wittmann S, et al., 2020, Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities. Cancers, 12(7): 1731.
Liu J, Lu Y, Dai Y, et al., 2022, A Comprehensive Analysis and Validation of Cuproptosis-Associated Genes Across Cancers: Overall Survival, the Tumor Microenvironment, Stemness Scores, and Drug Sensitivity. Frontiers in Genetics, 13: 939956.
Lukanović D, Herzog M, Kobal B, et al., 2020, The Contribution of Copper Efflux Transporters ATP7A and ATP7B to Chemoresistance and Personalized Medicine in Ovarian Cancer. Biomedicine & Pharmacotherapy, 129: 110401.
Kamiya T, 2022, Copper Biology in Health and Disease: Copper in the Tumor Microenvironment and Tumor Metastasis. Journal of Clinical Biochemistry and Nutrition, 71(1): 22.
Wan R, Pan L, Wang Q, et al., 2024, Decoding Gastric Cancer: Machine Learning Insights Into the Significance of COMMDs Family in Immunotherapy and Diagnosis. Journal of Cancer, 15(11): 3580.
Riera-Romo M, 2018, COMMD1: A Multifunctional Regulatory Protein. Journal of Cellular Biochemistry, 119(1): 34–51.
Maung MT, Carlson A, Olea-Flores M, et al., 2021, The Molecular and Cellular Basis of Copper Dysregulation and Its Relationship With Human Pathologies. The FASEB Journal, 35(9): 21810.
Karlsson H, Fryknäs M, Strese S, et al., 2017, Mechanistic Characterization of a Copper Containing Thiosemicarbazone with Potent Antitumor Activity. Oncotarget, 8(18): 30217.
Chen X, Mims J, Huang X, et al., 2018, Modulators of Redox Metabolism in Head and Neck Cancer. Antioxidants & Redox Signaling, 29(16): 1660–1690.
Boyd SD, Ullrich MS, Skopp A, et al., 2020, Copper Sources for Sod1 Activation. Antioxidants, 9(6): 500.
Mu W, Zhi Y, Zhou J, et al., 2024, Endoplasmic Reticulum Stress and Quality Control in Relation to Cisplatin Resistance in Tumor Cells. Frontiers in Pharmacology, 15: 1419468.
Qin X, Wang P, Liang H, et al., 2024, Curcumin Suppresses Copper Accumulation in Non-Small Cell Lung Cancer by Binding ATOX1. BMC Pharmacology and Toxicology, 25(1): 54.
Suraweera A, Duijf PH, Jekimovs C, et al., 2021, COMMD1, from the Repair of DNA Double Strand Breaks, to a Novel Anti-Cancer Therapeutic Target. Cancers, 13(4): 830.
Weaver BP, Zhang Y, Hiscox S, et al., 2010, Zip4 (Slc39a4) Expression is Activated in Hepatocellular Carcinomas and Functions to Repress Apoptosis, Enhance Cell Cycle and Increase Migration. PloS one, 5(10): e13158.
Allard D, Turcotte M, Stagg J, 2017, Targeting A2 Adenosine Receptors in Cancer. Immunology and Cell Biology, 95(4): 333–339.
Zhou Y, Lei D, Hu G, et al., 2022, A Cell Cycle-Related 13-mRNA Signature to Predict Prognosis in Hepatocellular Carcinoma. Frontiers in Oncology, 2022(12): 760190.
Li Y, 2020, Copper Homeostasis: Emerging Target for Cancer Treatment. IUBMB Life, 72(9): 1900–1908.
Zhalsanova IZ, Fonova E, Zhigalina D, et al., 2023, The ATOX1 Gene Role in Copper Metabolism and the Pathogenesis of Copper-Induced Diseases. Russian Journal of Genetics, 59(3): 242–250.
Zhang X, 2023, Copper Binding Proteins in Breast Cancer: Cellular and Molecular Mechanisms, thesis, Chalmers University of Technology.
Arnesano F, Natile G, 2021, Interference Between Copper Transport Systems and Platinum Drugs. Seminars in Cancer Biology, 75: 176–188.