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Cuproptosis as the new kryptonite of cancer: a copper-dependent novel cell death mechanism with promising implications for the treatment of hepatocellular carcinoma

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Abstract

Copper is an essential element for critical cellular functions such as mitochondrial respiration, cholesterol biosynthesis and immune response. Altered copper homeostasis has been associated with various disorders, including cancer. The copper overload is known to contribute to tumorigenesis, angiogenesis and metastasis, and recently it has been suggested that the elevated level of this element may also create vulnerability to a novel cell death mechanism, named cuproptosis. Excessive amount of copper in mitochondria binds to lipoylated enzymes of the TCA cycle and forms insoluble oligomers. The aggregation of these oligomers and subsequent iron–sulfur cluster protein loss results in proteotoxic stress and eventual cell death. Hepatocellular carcinoma is a common malignancy with a low survival rate, despite the available treatment options. The discovery of cuproptosis led many researchers to explore its potential use in hepatocellular cancer therapy due to the rich mitochondria content of hepatic cells. In this regard, a number of genomic studies were conducted to discover several cuproptosis-related genes and explored their association with prognosis, survival and immunotherapy response. This review brings together the available data on the relationship between cuproptosis and hepatocellular cancer for the first time, and highlights some of the potential biomarkers or target molecules that may be useful in the treatment.

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References

  • An P, Wei L-L, Zhao S, Sverdlov DY, Vaid KA, Miyamoto M, Kuramitsu K, Lai M, Popov YV (2020) Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nat Commun 11:2362

    CAS  PubMed  PubMed Central  Google Scholar 

  • Baldari S, Di Rocco G, Heffern MC, Su TA, Chang CJ, Toietta G (2019) Effects of copper chelation on BRAFV600E positive colon carcinoma cells. Cancers (basel) 11:659

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bandmann O, Weiss KH, Kaler SG (2015) Wilson’s disease and other neurological copper disorders. Lancet Neurol 14:103–113

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bian C, Zheng Z, Su J, Chang S, Yu H, Bao J, Xin Y, Jiang X (2023) Copper homeostasis and cuproptosis in tumor pathogenesis and therapeutic strategies. Front Pharmacol 14:1–15

    Google Scholar 

  • Chen S, Liu P, Zhao L, Han P, Liu J, Yang H, Li J (2022) A novel cuproptosis-related prognostic lncRNA signature for predicting immune and drug therapy response in hepatocellular carcinoma. Front Immunol 13:1–13

    Google Scholar 

  • Chen Y, Tang L, Huang W, Abisola FH, Zhang Y, Zhang G, Yao L (2023) Identification of a prognostic cuproptosis-related signature in hepatocellular carcinoma. Biol Direct 18:4

    PubMed  PubMed Central  Google Scholar 

  • Cong T, Luo Y, Liu Y, Yang C, Yang H, Li Y, Li J, Li X (2022) Cuproptosis-related immune checkpoint gene signature: prediction of prognosis and immune response for hepatocellular carcinoma. Front Genet 13:1–18

    Google Scholar 

  • Darvin P, Toor SM, Sasidharan Nair V, Elkord E (2018) Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 50:1–11

    PubMed  Google Scholar 

  • Davis CI, Gu X, Kiefer RM, Ralle M, Gade TP, Brady DC (2020) Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation. Metallomics 12:1995–2008

    CAS  PubMed  Google Scholar 

  • Fang A, Chen P, Wang X, Liu Z, Zhang D, Luo Y, Liao G, Long J, Zhong R, Zhou Z, Xu Y, Xu X, Ling W, Chen M, Zhang Y, Zhu H (2019) Serum copper and zinc levels at diagnosis and hepatocellular carcinoma survival in the Guangdong liver cancer cohort. Int J Cancer 144:2823–2832

    CAS  PubMed  Google Scholar 

  • Feng Y, Zeng J-W, Ma Q, Zhang S, Tang J, Feng J-F (2020) Serum copper and zinc levels in breast cancer: a meta-analysis. J Trace Elem Med Biol 62:126629

    CAS  PubMed  Google Scholar 

  • Gombart AF, Pierre A, Maggini S (2020) A review of micronutrients and the immune system-working in harmony to reduce the risk of infection. Nutrients 12:236

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gunjan D, Shalimar NN, Kedia S, Nayak B, Paul SB, Gamanagatti SR, Acharya SK (2017) Hepatocellular carcinoma: an unusual complication of longstanding wilson disease. J Clin Exp Hepatol 7:152–154

    PubMed  Google Scholar 

  • Guo J, Cheng J, Zheng N, Zhang X, Dai X, Zhang L, Hu C, Wu X, Jiang Q, Wu D, Okada H, Pandolfi PP, Wei W (2021) Copper promotes tumorigenesis by activating the PDK1-AKT oncogenic pathway in a copper transporter 1 dependent manner. Adv Sci. https://doi.org/10.1002/advs.202004303

    Article  Google Scholar 

  • Guo B, Yang F, Zhang L, Zhao Q, Wang W, Yin L, Chen D, Wang M, Han S, Xiao H, Xing N (2023) Cuproptosis induced by ROS responsive nanoparticles with elesclomol and copper combined with αPD-L1 for enhanced cancer immunotherapy. Adv Mater 35:1–15

    Google Scholar 

  • Gupta A, Lutsenko S (2009) Human copper transporters: mechanism, role in human diseases and therapeutic potential. Future Med Chem 1:1125–1142

    CAS  PubMed  Google Scholar 

  • Han IW, Jang J-Y, Kwon W, Park T, Kim Y, Lee KB, Kim S-W (2017) Ceruloplasmin as a prognostic marker in patients with bile duct cancer. Oncotarget 8:29028–29037

    PubMed  PubMed Central  Google Scholar 

  • Juloski JT, Rakic A, Ćuk VV, Ćuk VM, Stefanović S, Nikolić D, Janković S, Trbovich AM, De Luka SR (2020) Colorectal cancer and trace elements alteration. J Trace Elem Med Biol 59:126451

    CAS  PubMed  Google Scholar 

  • Kannappan V, Ali M, Small B, Rajendran G, Elzhenni S, Taj H, Wang W, Dou QP (2021) Recent advances in repurposing disulfiram and disulfiram derivatives as copper-dependent anticancer agents. Front Mol Biosci 8:1–20

    Google Scholar 

  • Ke C, Dai S, Xu F, Yuan J, Fan S, Chen Y, Yang L, Li Y (2023) Cuproptosis regulatory genes greatly contribute to clinical assessments of hepatocellular carcinoma. BMC Cancer 23:25

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lelièvre P, Sancey L, Coll J-L, Deniaud A, Busser B (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 (basel) 12:3594

    PubMed  Google Scholar 

  • Li Y (2020) Copper homeostasis: emerging target for cancer treatment. IUBMB Life 72:1900–1908

    CAS  PubMed  Google Scholar 

  • Liangyu Z, Bochao Z, Guoquan Y, Yuan Z, Heng L, Hanyu Z (2023) Bioinformatics prediction and experimental verification identify cuproptosis-related lncRNA as prognosis biomarkers of hepatocellular carcinoma. Biochem Biophys Rep 35:101502

    PubMed  PubMed Central  Google Scholar 

  • Liu C, Wu S, Lai L, Liu J, Guo Z, Ye Z, Chen X (2023) Comprehensive analysis of cuproptosis-related lncRNAs in immune infiltration and prognosis in hepatocellular carcinoma. BMC Bioinform 24:1–22

    Google Scholar 

  • Luo L, Hu X, Huang A, Liu X, Wang L, Du T, Liu L, Li M (2022) A noval established cuproptosis-associated LncRNA signature for prognosis prediction in primary hepatic carcinoma. Evid-Based Complement Altern Med. https://doi.org/10.1155/2022/2075638

    Article  Google Scholar 

  • Mao S, Huang S (2013) Zinc and copper levels in bladder cancer: a systematic review and meta-analysis. Biol Trace Elem Res 153:5–10

    PubMed  Google Scholar 

  • Mukae Y, Ito H, Miyata Y, Araki K, Matsuda T, Aibara N, Nakamura Y, Matsuo T, Sakai H, Ohyama K (2021) Ceruloplasmin levels in cancer tissues and urine are significant biomarkers of pathological features and outcome in bladder cancer. Anticancer Res 41:3815–3823

    CAS  PubMed  Google Scholar 

  • Porcu C, Antonucci L, Barbaro B, Illi B, Nasi S, Martini M, Licata A, Miele L, Grieco A, Balsano C (2018) Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma. Oncotarget 9:9325–9343

    PubMed  PubMed Central  Google Scholar 

  • Ruiz LM, Libedinsky A, Elorza AA (2021) Role of copper on mitochondrial function and metabolism. Front Mol Biosci 8:1–17

    Google Scholar 

  • Statello L, Guo C-J, Chen L-L, Huarte M (2021) Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 22:96–118

    CAS  PubMed  Google Scholar 

  • Tsang T, Posimo JM, Gudiel AA, Cicchini M, Feldser DM, Brady DC (2020) Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. Nat Cell Biol 22:412–424

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsvetkov P, Detappe A, Cai K, Keys HR, Brune Z, Ying W, Thiru P, Reidy M, Kugener G, Rossen J, Kocak M, Kory N, Tsherniak A, Santagata S, Whitesell L, Ghobrial IM, Markley JL, Lindquist S, Golub TR (2019) Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol 15:681–689

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch-Cohen L, Humeidi R, Spangler RD, Eaton JK, Frenkel E, Kocak M, Corsello SM, Lutsenko S, Kanarek N, Santagata S, Golub TR (2022) Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375:1254–1261

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vairo FP, Chwal BC, Perini S, Ferreira MAP, de Freitas Lopes AC, Saute JAM (2019) A systematic review and evidence-based guideline for diagnosis and treatment of Menkes disease. Mol Genet Metab 126:6–13

    CAS  PubMed  Google Scholar 

  • Voli F, Valli E, Lerra L, Kimpton K, Saletta F, Giorgi FM, Mercatelli D, Rouaen JRC, Shen S, Murray JE, Ahmed-Cox A, Cirillo G, Mayoh C, Beavis PA, Haber M, Trapani JA, Kavallaris M, Vittorio O (2020) Intratumoral copper modulates PD-L1 expression and influences tumor immune evasion. Cancer Res 80:4129–4144

    CAS  PubMed  Google Scholar 

  • Wang H, Wang N, Tang Z, Liu Q, Nie S, Tao W (2023a) An 8-gene predicting survival model of hepatocellular carcinoma (HCC) related to pyroptosis and cuproptosis. Hereditas 160:30

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Lu K, Jiang X, Wei Q, Zhu L, Wang X, Jin H, Feng L (2023b) Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer. J Exp Clin Cancer Res 42:142

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Zhou M, Liu Y, Si Z (2023c) Cope with copper: from copper linked mechanisms to copper-based clinical cancer therapies. Cancer Lett 561:216157

    CAS  PubMed  Google Scholar 

  • Wu Z, Lv G, Xing F, Xiang W, Ma Y, Feng Q, Yang W, Wang H (2023) Copper in hepatocellular carcinoma: a double-edged sword with therapeutic potentials. Cancer Lett 571:216348

    CAS  PubMed  Google Scholar 

  • Xie Y, Zhang W, Sun J, Sun L, Meng F, Yu H (2022) A novel cuproptosis-related immune checkpoint gene signature identification and experimental validation in hepatocellular carcinoma. Sci Rep 12:18514

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xie J, Yang Y, Gao Y, He J (2023) Cuproptosis: mechanisms and links with cancers. Mol Cancer 22:46

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yan C, Niu Y, Ma L, Tian L, Ma J (2022) System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma. J Transl Med 20:452

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang G, Sun J, Zhang X (2022a) A novel Cuproptosis-related LncRNA signature to predict prognosis in hepatocellular carcinoma. Sci Rep 12:11325

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Ma L, Zhou H, Zhou Y, Liu S, Li Q (2022b) A prognostic signature of cuproptosis and TCA-related genes for hepatocellular carcinoma. Front Oncol 12:1–14

    CAS  Google Scholar 

  • Zhao X, Chen J, Yin S, Shi J, Zheng M, He C, Meng H, Han Y, Han J, Guo J, Yuan Z, Wang Y (2022) The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis. Front Oncol 12:1–18

    Google Scholar 

  • Zowczak M, Iskra M, Torliński L, Cofta S (2001) Analysis of serum copper and zinc concentrations in cancer patients. Biol Trace Elem Res 82:001–008

    CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Pharmacy, Department of Biochemistry, Ankara Medipol University, 06050, Altindag, Ankara, Turkey

    Erva Ozkan

  2. Faculty of Pharmacy, Department of Biochemistry, Ankara University, 06560, Anadolu, Ankara, Turkey

    Filiz Bakar-Ates

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  1. Erva Ozkan
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  2. Filiz Bakar-Ates
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EO: Writing, data collection and editing. FB-A: Supervision, writing and editing.

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Correspondence to Erva Ozkan.

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Ozkan, E., Bakar-Ates, F. Cuproptosis as the new kryptonite of cancer: a copper-dependent novel cell death mechanism with promising implications for the treatment of hepatocellular carcinoma. J Cancer Res Clin Oncol 149, 17663–17670 (2023). https://doi.org/10.1007/s00432-023-05456-w

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