Strategies to combat cancer drug resistance: focus on copper metabolism and cuproptosis

Abstract

Cancer cells often develop tolerance to chemotherapy, targeted therapy, and immunotherapy drugs either before or during treatment. The significant heterogeneity among various tumors poses a critical challenge in modern cancer research, particularly in overcoming drug resistance. Copper, as an essential trace element in the body, participates in various biological processes of diseases, including cancers. The growth of many types of tumor cells exhibits a heightened dependence on copper. Thus, targeting copper metabolism or inducing cuproptosis may be potential ways to overcome cancer drug resistance. Copper chelators have shown potential in overcoming cancer drug resistance by targeting copper-dependent processes in cancer cells. In contrast, copper ionophores, copper-based nanomaterials, and other small molecules have been used to induce copper-dependent cell death (cuproptosis) in cancer cells, including drug-resistant tumor cells. This review summarizes the regulation of copper metabolism and cuproptosis in cancer cells and the role of copper metabolism and cuproptosis in cancer drug resistance, providing ideas for overcoming cancer resistance in the future.

Keywords: Cuproptosis; cancer; cell death; copper; drug resistance; metabolism.

Figure 1

Copper redox, oxidation, and absorbance in cells. ZnT1 directly transports extracellular Cu²⁺ into cells. Extracellular Cu²⁺ could be reduced to Cu⁺ via STEAP and then transported into cells via SLC31A1, while ATP7B opposes this process via excreting Cu⁺. Intracellular Cu⁺ is absorbed into lysosomes and mitochondria via SLC46A3 and ATP7A, respectively. ZnT1: Solute carrier family 30 member 1/Slc30a1, a zinc and copper transporter; STEAP: 6-transmembrane epithelial antigen of prostate, comprises STEAP1, STEAP2, STEAP3, and STEAP4; Dcytb: duodenal cytochrome b; SLC31A1: solute carrier family 31 member 1, Ctr1: copper transport protein 1; ATP7B: ATPase copper-transporting beta; SLC46A3: solute carrier family 46 member 3; ATP7A: ATPase copper-transporting alpha.

Figure 2

The signaling pathways of copper metabolism. Extracellular Cu²⁺ is reduced to Cu⁺ via STEAP. Both Cu²⁺ and Cu⁺ are transported into cells via corresponding transporters. Intracellular copper is sequestrated via MT1/2 or GSH or transported via COX17, CCS, SOD1, ATOX1, MEMO1, and ATP7B. Mitochondrial copper functions via SCO1, SCO2, MT-CO1, MT-CO2, and COX11, while nuclear copper can regulate gene expression. STEAP: 6-Transmembrane epithelial antigen of prostate, comprises STEAP1, STEAP2, STEAP3 and STEAP4; MT1/2: metallothionein 1/2; GSH: glutathione; COX17: cytochrome c oxidase copper chaperone COX17; CCS: copper chaperone for superoxide dismutase; SOD1: superoxide dismutase 1; ATOX1: antioxidant 1 copper chaperone; MEMO1: mediator of cell motility 1; ATP7B: ATPase copper-transporting beta; SCO1: synthesis of cytochrome C oxidase 1; SCO2: synthesis of cytochrome C oxidase 1; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MT-CO2: mitochondrially encoded cytochrome c oxidase II; COX11: cytochrome c oxidase copper chaperone COX11.

Figure 3

The mechanism of cuproptosis. Copper ionophore elesclomol directly transports Cu²⁺ into cells and then Cu²⁺ is reduced to Cu⁺ via FDX1. After the reduction of Cu²⁺ into Cu⁺ via STEAP, Cu⁺ is pumped into cells via SLC31A1. FDX1 and LIAS induce DLAT lipoylation and aggregation, inducing the damage of the TCA cycle. As such, cells are dead via cuproptosis. FDX1: Ferredoxin 1; STEAP: 6-transmembrane epithelial antigen of prostate, comprises STEAP1, STEAP2, STEAP3, and STEAP4; SLC31A1: solute carrier family 31 member 1; LIAS: lipoic acid synthetase; DLAT: dihydrolipoamide S-acetyltransferase; TCA: tricarboxylic acid; LA: lipoic acid.

Figure 4

Copper ionophores and cuproptosis combat tumor drug resistance. Copper ionophore elesclomol overcomes cisplatin, 5-fluorouracil and vemurafenib resistance in the indicated cancers. Copper ionophore disulfiram bypasses cisplatin, 5-fluorouracil, paclitaxel and gemcitabine resistance in the indicated tumors. Cuproptosis inducers combat cisplatin, proteasome inhibitors, oxaliplatin, docetaxel, enzalutamide and anti-PD-L1 resistance in the indicated cancers. PD-L1: CD274 molecule.