Regulatory Roles of Copper Metabolism and Cuproptosis in Human Cancers

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Apr 10

PMID 37035162

Authors

Zhe Wang

Dekui Jin

Shuaishuai Zhou

Niujing Dong

Yuting Ji

Peng An

Jiaping Wang

Yongting Luo

Junjie Luo

Affiliations

Soon will be listed here.

Abstract

Copper is an essential micronutrient for human body and plays a vital role in various biological processes including cellular respiration and free radical detoxification. Generally, copper metabolism in the body is in a stable state, and there are specific mechanisms to regulate copper metabolism and maintain copper homeostasis. Dysregulation of copper metabolism may have a great connection with various types of diseases, such as Wilson disease causing copper overload and Menkes disease causing copper deficiency. Cancer presents high mortality rates in the world due to the unlimited proliferation potential, apoptosis escape and immune escape properties to induce organ failure. Copper is thought to have a great connection with cancer, such as elevated levels in cancer tissue and serum. Copper also affects tumor progression by affecting angiogenesis, metastasis and other processes. Notably, cuproptosis is a novel form of cell death that may provide novel targeting strategies for developing cancer therapy. Copper chelators and copper ionophores are two copper coordinating compounds for the treatment of cancer. This review will explore the relationship between copper metabolism and cancers, and clarify copper metabolism and cuproptosis for cancer targeted therapy.

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References

Khan M, Mamou F, Schipper M, May K, Kwitny A, Warnat A . Combination tetrathiomolybdate and radiation therapy in a mouse model of head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2006; 132(3):333-8. DOI: 10.1001/archotol.132.3.333. View

van Golen K, Bao L, Brewer G, Pienta K, Kamradt J, Livant D . Suppression of tumor recurrence and metastasis by a combination of the PHSCN sequence and the antiangiogenic compound tetrathiomolybdate in prostate carcinoma. Neoplasia. 2002; 4(5):373-9. PMC: 1564117. DOI: 10.1038/sj.neo.7900258. View

Shanbhag V, Gudekar N, Jasmer K, Papageorgiou C, Singh K, Petris M . Copper metabolism as a unique vulnerability in cancer. Biochim Biophys Acta Mol Cell Res. 2020; 1868(2):118893. PMC: 7779655. DOI: 10.1016/j.bbamcr.2020.118893. View

Blockhuys S, Zhang X, Wittung-Stafshede P . Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration. Proc Natl Acad Sci U S A. 2020; 117(4):2014-2019. PMC: 6995000. DOI: 10.1073/pnas.1910722117. View

Chen J, Jiang Y, Shi H, Peng Y, Fan X, Li C . The molecular mechanisms of copper metabolism and its roles in human diseases. Pflugers Arch. 2020; 472(10):1415-1429. DOI: 10.1007/s00424-020-02412-2. View

Cater M, Haupt Y . Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): therapeutic indication for prostate cancer. Biochem J. 2011; 436(2):481-91. DOI: 10.1042/BJ20110123. View

Tisato F, Marzano C, Porchia M, Pellei M, Santini C . Copper in diseases and treatments, and copper-based anticancer strategies. Med Res Rev. 2009; 30(4):708-49. DOI: 10.1002/med.20174. View

Itoh S, Kim H, Nakagawa O, Ozumi K, Lessner S, Aoki H . Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation. J Biol Chem. 2008; 283(14):9157-67. PMC: 2431038. DOI: 10.1074/jbc.M709463200. View

Yaman M, Kaya G, Yekeler H . Distribution of trace metal concentrations in paired cancerous and non-cancerous human stomach tissues. World J Gastroenterol. 2007; 13(4):612-8. PMC: 4065986. DOI: 10.3748/wjg.v13.i4.612. View

10.

Denoyer D, Clatworthy S, Cater M . Copper Complexes in Cancer Therapy. Met Ions Life Sci. 2018; 18. DOI: 10.1515/9783110470734-022. View

11.

Ohgami R, Campagna D, McDonald A, Fleming M . The Steap proteins are metalloreductases. Blood. 2006; 108(4):1388-94. PMC: 1785011. DOI: 10.1182/blood-2006-02-003681. View

12.

Kaiafa G, Saouli Z, Diamantidis M, Kontoninas Z, Voulgaridou V, Raptaki M . Copper levels in patients with hematological malignancies. Eur J Intern Med. 2012; 23(8):738-41. DOI: 10.1016/j.ejim.2012.07.009. View

13.

Liaw K, Lee P, Wu F, Tsai J, Lin-Shiau S . Zinc, copper, and superoxide dismutase in hepatocellular carcinoma. Am J Gastroenterol. 1997; 92(12):2260-3. View

14.

Wadhwa S, Mumper R . D-penicillamine and other low molecular weight thiols: review of anticancer effects and related mechanisms. Cancer Lett. 2013; 337(1):8-21. DOI: 10.1016/j.canlet.2013.05.027. View

15.

Bian Z, Fan R, Xie L . A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma. Genes (Basel). 2022; 13(5). PMC: 9141858. DOI: 10.3390/genes13050851. View

16.

Fang A, Chen P, Wang X, Liu Z, Zhang D, Luo Y . Serum copper and zinc levels at diagnosis and hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort. Int J Cancer. 2018; 144(11):2823-2832. DOI: 10.1002/ijc.31991. View

17.

Pavithra V, Sathisha T, Kasturi K, Mallika D, Amos S, Ragunatha S . Serum levels of metal ions in female patients with breast cancer. J Clin Diagn Res. 2015; 9(1):BC25-c27. PMC: 4347069. DOI: 10.7860/JCDR/2015/11627.5476. View

18.

Tsvetkov P, Detappe A, Cai K, Keys H, Brune Z, Ying W . Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol. 2019; 15(7):681-689. PMC: 8183600. DOI: 10.1038/s41589-019-0291-9. View

19.

Cox C, Merajver S, Yoo S, Dick R, Brewer G, Lee J . Inhibition of the growth of squamous cell carcinoma by tetrathiomolybdate-induced copper suppression in a murine model. Arch Otolaryngol Head Neck Surg. 2003; 129(7):781-5. DOI: 10.1001/archotol.129.7.781. View

20.

Khan M, Miller M, Taylor J, Gill N, Dick R, van Golen K . Radiotherapy and antiangiogenic TM in lung cancer. Neoplasia. 2002; 4(2):164-70. PMC: 1550318. DOI: 10.1038/sj.neo.7900218. View