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Review
. 2023 Mar 7;22(1):46.
doi: 10.1186/s12943-023-01732-y.

"V体育官网入口" Cuproptosis: mechanisms and links with cancers

Jiaming Xie #  1   2 , Yannan Yang #  1   2 , Yibo Gao  3   4 , Jie He  5   6   7
Affiliations
Review

Cuproptosis: mechanisms and links with cancers (V体育平台登录)

VSports最新版本 - Jiaming Xie et al. Mol Cancer. .

V体育官网入口 - Abstract

Cuproptosis was a copper-dependent and unique kind of cell death that was separate from existing other forms of cell death. The last decade has witnessed a considerable increase in investigations of programmed cell death, and whether copper induced cell death was an independent form of cell death has long been argued until mechanism of cuproptosis has been revealed. After that, increasing number of researchers attempted to identify the relationship between cuproptosis and the process of cancer. Thus, in this review, we systematically detailed the systemic and cellular metabolic processes of copper and the copper-related tumor signaling pathways. Moreover, we not only focus on the discovery process of cuproptosis and its mechanism, but also outline the association between cuproptosis and cancers VSports手机版. Finally, we further highlight the possible therapeutic direction of employing copper ion ionophores with cuproptosis-inducing functions in combination with small molecule drugs for targeted therapy to treat specific cancers. .

Keywords: Cancer; Copper; Cuproptosis; Drug resistance; Immunotherapy; Metabolism; Targeted therapy V体育安卓版. .

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Timeline illustrating the discovery of cuproptosis. The historical events contributing to the discovery of cuproptopsis and oncological research advances of copper associated cell death are depicted in the timeline
Fig. 2
Fig. 2
Schematic of systemic and cellular copper metabolism. The body absorbs copper mostly through the small intestine, where it is then transported by blood to the liver for excretion into the bile. In tumor cells, interactions between several proteins maintain copper homeostasis. The entry and departure of copper ions into and out of the cell are controlled by the copper ion transporters SLC31A1 and ATP7B, whereas the transit of copper ions through the outer and inner mitochondrial membranes is controlled by COX17 and SLC25A3, respectively. Copper ions entering the cytoplasm and mitochondrial intermembrane space bind to GSH and MT or form copper-containing molecular chaperones such as SOD1 which is crucial for proper function of copper. To sustain normal cellular functions, COA6, SCO1 and SCO2 work together to mediate the transfer of copper to COX in the mitochondrial intermembrane space
Fig. 3
Fig. 3
Copper and cancer singnaling pathways. Copper is strongly associated with the process of cancer and impacts them in a direct or indirect ways. Copper directly binds or activates EGFR, PDK1 or PI3K to promotes tumorigenesis. Copper also influences MAPK and autophagic pathways or indirectly changes c-Myc stability to influence tumor growth. Copper ions indirectly promotes HIFα or indirectly inhibits the Notch pathway ligand Jagged1 thus promoting vascular neoplastic migration. In addition, copper can also regulate PDE3B or S6K1 and thus modulates tumor metabolism
Fig. 4
Fig. 4
Schematic of cuproptosis mechanism. Cuproptosis can be triggered by elevating intracellular free copper ion concentration in four ways involved in the absorption, export and storage of copper: (1) treatment with copper ionophores, which shuttle copper into the cell directly, such as ES and DSF; (2) overexpression of SLC31A1, the copper permease specific for reduced copper ion; (3) inhibition of glutathione (GSH) synthesis through BSO, without which free copper ion was released; (4) knockdown of ATP7B, decreasing copper export. Excessive Cu(I) binds to lipoyled DLAT and further leads to DLAT oligomerization, which, together with copper-induced reduction of Fe-S stability or inactivation of Npl4-p97, can lead to the onset of copper-induced cell death. ES elesclomol, DSF disulfiram, BSO L-Buthionine-sulfoximine
Fig. 5
Fig. 5
Cuproptosis related genes and cancer signaling pathways. Cuproptosis related genes occupy an important position in the tumor signaling pathways which have significant relevance to various processes of cancers, including proliferation, genomic instability, evading apoptosis, sustained angiogenesis and insensitive to antigrowth signals. The molecules linked together to accomplish the function by creating the complex, while the molecules framed by the dotted line cooperate to achieve the function. Essential genes in CRG-related cancer pathways and associated cancer processes are listed, CRGs are marked in orange
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