Copper homeostasis and cuproptosis in tumor pathogenesis and therapeutic strategies

Abstract

Copper is an indispensable micronutrient for the development and replication of all eukaryotes, and its redox properties are both harmful and beneficial to cells. An imbalance in copper homeostasis is thought to be involved in carcinogenesis. Importantly, cancer cell proliferation, angiogenesis, and metastasis cannot be separated from the effects of copper. Cuproposis is a copper-dependent form of cell death that differs from other existing modalities of regulatory cell death. The role of cuproptosis in the pathogenesis of the nervous and cardiovascular systems has been widely studied; however, its impact on malignant tumors is yet to be fully understood from a clinical perspective. Exploring signaling pathways related to cuproptosis will undoubtedly provide a new perspective for the development of anti-tumor drugs in the future. Here, we systematically review the systemic and cellular metabolic processes of copper and the regulatory mechanisms of cuproptosis in cancer. In addition, we discuss the possibility of targeting copper ion drugs to prolong the survival of cancer patients, with an emphasis on the most representative copper ionophores and chelators. We suggest that attention should be paid to the potential value of copper in the treatment of specific cancers.

Keywords: cancer therapeutics; carcinogenesis; copper homeostasis; cuproptosis; drug.

FIGURE 1

Schematic of copper homeostasis in mammalian cells.CP is the major protein carrier for exchangeable copper in blood plasma for circulation and delivery to organ and tissue systems. Extracellular Cu²⁺ is reduced to Cu¹⁺ by STEAP, which in turn is transported into the cell by CTR1. Intracellular Cu¹⁺ binds to different chaperone proteins to exert its unique functions. CCS delivers Cu¹⁺ to SOD1 in the cytoplasm to clear free radicals. In the mitochondrial membrane space, COX17 transports Cu¹⁺ to CCO to activate enzyme activity in the respiratory chain. MT1/2 and GSH are copper repositories that can bind Cu¹⁺. Part of the Cu¹⁺ carried by ATOX1 enters the nucleus to participate in gene expression, and the other part is pumped into the lumen of the TGN by ATP7A/B. When cytosolic Cu levels are high, Cu¹⁺ in small intestinal cells is discharged into the portal circulation via ATP7A, while Cu¹⁺ in liver cells is secreted into bile in the form of vesicles through ATP7B. The maintenance of cellular physiological functions is inseparable from copper homeostasis. Abbreviations: CP, ceruloplasmin; STEAP, the six-transmembrane epithelial antigen of the prostate; CTR1, copper transporter 1; CCS, copper chaperone for superoxide dismutase; SOD1, superoxide dismutase 1; MTI/2, metallothionein 1/2; GSH, glutathione; ATOX1, antioxidant 1 copper chaperone; ATP7A/B, ATPase copper transporter 7A/B; TGN, trans-Golgi network.

FIGURE 2

Overview of crosstalk between cuproptosis and ferroptosis.Cuproptosis inducers (CINs) elesclomol and disulfiram carry Cu²⁺ into the cell, which is reduced to Cu¹⁺ under FDX1. Subsequent lipoylated proteins oligomerization and Fe-S cluster proteins loss trigger proteotoxic stress, and eventually cell death. As for ferroptosis, it is mediated by excess Fe²⁺ as well as abrogation of GSH biosynthesis and inactivation of GPX4 through causing lipid peroxidation. GSH, like copper chelator, inhibits copper death. However, ferroptosis inducers sorafenib and erastin can enhance cuproptosis, with potential mechanisms including inhibition of FDX1 degradation and reduction of GSH synthesis. Abbreviations: GSH, glutathione; GPX4, glutathione peroxidase 4; FDX1, ferredoxin 1; LIAS, lipoic acid synthetase; TFR, transferring receptor; SLC31A1, solute carrier family 31 member 1; SLC7A11, solute carrier family 7 member 11.

FIGURE 3

Summary of the relationship between copper signaling and cancer. Copper is involved in almost all fundamental processes of cancers. The pro-cancer role of copper can be summarized in four aspects: inducing tumorigenesis, promoting tumor growth, regulating angiogenesis, and assisting tumor metastasis, the details of which are presented below. Abbreviations: RTK, receptor tyrosine kinase; ERK1/2, extracellular signal-regulated kinase 1/2; ATK, agammaglobulinaemia tyrosine kinase; PI3K, phosphoinositide-3-kinase; PDK1, 3-phosphoinositide dependent protein kinase 1; FoxO1a, forkhead box O1a; LOX, lysyl oxidase; MEK1/2, mitogen-activated protein kinase kinase 1/2; MEMO1, mediator of ErbB2-driven cell motility 1; PD-L1, programmed death ligand 1; VEGF, vascular endothelial growth factor; GPER, G-protein estrogen receptor; FGF2, fibroblast growth factor 2; TNF-α, tumor necrosis factor α.