Cuproptosis: mechanisms and links with cancers

Molecular Cancer (2023) 22:46 Xie et al. Molecular Cancer https://doi.org/10.1186/s12943-023-01732-y Open Access REVIEW Cuproptosis: mechanisms and links with cancers Jiaming Xie1,2†, Yannan Yang1,2†, Yibo Gao3,4* and Jie He1,2,4* 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. Finally, we further highlight the possible therapeutic direction of employing copper ion ionophores with cuproptosisinducing functions in combination with small molecule drugs for targeted therapy to treat specific cancers. Keywords Cuproptosis, Copper, Cancer, Targeted therapy, Immunotherapy, Drug resistance, Metabolism † Jiaming Xie and Yannan Yang contributed equally to this work. *Correspondence: Yibo Gao Jie He 1 Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 2 State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 3 Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China 4 Laboratory of Translational Medicine, National Cancer Center/National, Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 101399, China Background In the recent years, cuproptosis, a novel form of regulated cell death which is copper dependent has been identified [1, 2], may be implicated in the process of various cancers. Copper is a trace element in the human body and has been strongly associated with various signaling pathways and tumor-related biological behaviors [3]. Moreover, excess copper can lead to cell death, and for a long time the mechanisms and specific forms of copperinduced cell death have remained unclear. Until early this year, it has been suggested by a recent study that cuproptosis is an independent form of cell death, which was considered to be highly correlated with mitochondrial respiration and lipoic acid(LA) pathway [4]. We briefly summarize some of the findings on copper-induced cell death that have driven progress in the field (Fig. 1). A considerable number of researchers focusing on the pivotal relationship between cuproptosis and cancers. On the one hand, cancer has multiple types, with sufficient multi-omics data. On the other hand, cuproptosis © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xie et al. Molecular Cancer (2023) 22:46 Page 2 of 30 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 is highly related to cellular metabolism, and certain cancer types usually exhibits high aerobic respiration levels. Some tumor types such as melanoma, breast cancer and leukemia [5, 6], some cancers with tumor stem cells [7, 8] and some drug-resistant tumors exhibit a high mitochondrial metabolic state [9–13]. Tumor cells treated with certain antitumor drugs such as proteasome inhibitors(PI) have also been found to exhibit higher mitochondrial metabolism [14, 15]. A growing number of researchers focusing on the vital link between cuproptosis and cancer process through bioinformatic analysis. Some studies have focused on the relationship between expression levels of cuproptosis key genes (CKGs), genes identified and validated in the previous studies of Tsvetkov et al., and tumor prognosis. To avoid the effects of gene interactions, some investigators have constructed Cuproptosis-related signatures by cuproptosis related genes (CRGs) to identify the association of Cuproptosis with cancer. Copper ionophores played a major contribution in the discovery of cuproptosis, and have been considered for possible use in antitumor therapy in the past [16, 17]. However, their specific mechanisms and applicable populations have not been fully analyzed. With the discovery of the cuproptosis, the interactions between these drugs, copper and the mitochondria are becoming clear, which makes the antitumor clinical application of these drugs possible. This review focusing on discovery of the mechanism of cuproptosis and the pivotal relationship between cuproptosis and cancers. We aimed to provide possible directions for future studies related to cuproptosis and cancers. Systemic and cellular copper homeostasis Copper, a kind of indispensable transition metal, has two sides for cell. On the one hand, it served as co-factor for many enzymes by donating or receipting electronics [3], on the other hand, the accumulation of copper can lead to a series of cellular metabolic dysfunctions and eventually cell death [18]. People mainly obtain copper from food, out of which organ meats and shellfish tend to be the richest food sources of (...truncated)