Cuproptosis in cancer: biological implications and therapeutic opportunities

(2024) 29:91 Li et al. Cellular & Molecular Biology Letters https://doi.org/10.1186/s11658-024-00608-3 Cellular & Molecular Biology Letters Open Access REVIEW Cuproptosis in cancer: biological implications and therapeutic opportunities Liping Li1, Houfeng Zhou1 and Chenliang Zhang2*    *Correspondence: 1 Department of Pharmacy, Chengdu Fifth People’s Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China 2 Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of China Abstract Cuproptosis, a newly identified copper (Cu)-dependent form of cell death, stands out due to its distinct mechanism that sets it apart from other known cell death pathways. The molecular underpinnings of cuproptosis involve the binding of Cu to lipoylated enzymes in the tricarboxylic acid cycle. This interaction triggers enzyme aggregation and proteotoxic stress, culminating in cell death. The specific mechanism of cuproptosis has yet to be fully elucidated. This newly recognized form of cell death has sparked numerous investigations into its role in tumorigenesis and cancer therapy. In this review, we summarized the current knowledge on Cu metabolism and its link to cancer. Furthermore, we delineated the molecular mechanisms of cuproptosis and summarized the roles of cuproptosis-related genes in cancer. Finally, we offered a comprehensive discussion of the most recent advancements in Cu ionophores and nanoparticle delivery systems that utilize cuproptosis as a cutting-edge strategy for cancer treatment. Keywords: Copper, Cuproptosis, Tumorigenesis, Tumor therapy, Metabolism, Drug resistance Introduction Copper (Cu) is an important micronutrient in the human body that is vital in regulating various signaling pathways and associated biological processes, including mitochondrial respiration, detoxification of free radicals, and angiogenesis [1, 2]. In biological systems, copper exists in two oxidation states, i.e., divalent copper ion (Cu2+) and monovalent copper (Cu+). Imbalances in Cu homeostasis can contribute to the development of certain diseases, like Wilson’s disease caused by Cu overload and Menkes disease caused by Cu deficiency [2]. In the 1980s, it has been found that excessive Cu accumulation resulted in cell death [3]. Furthermore, Cu ionophores, which are lipid-soluble molecules that bind to Cu ions and transport them into cells, were discovered to induce cell death in tumor cells and have been used in clinical trials [4–6]. However, the molecular mechanism and specific form of cell death induced by Cu and Cu ionophores remained unclear for a long time. It was not until 2022 that Tsvetkov et al. unveiled a new form of cell death triggered by Cu called cuproptosis [7], which is independent of known forms of cell death like apoptosis, © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/. Li et al. Cellular & Molecular Biology Letters (2024) 29:91 ferroptosis, autophagy, and necrosis. Regarding the molecular mechanism, Tsvetkov et al. found a strong association between cuproptosis and mitochondrial respiration and the lipoic acid (LA) pathway. The binding of Cu to components involved in lipoacylation in the tricarboxylic acid (TCA) cycle leads to their aggregation and downregulation of Fe–S cluster proteins, ultimately inducing proteotoxic stress and cell death [7]. Through genome-wide knockout screens and individual gene knockout studies, Tsvetkov et al. identified several key regulatory genes involved in cuproptosis [7]. Research has revealed the dichotomous role of Cu in tumorigenesis, progression, and therapeutic interventions. On one hand, elevated levels of Cu ions have been found to promote tumor growth, metastasis, and angiogenesis in various malignant tumors [8, 9], while on the other hand, excessive Cu ions can also induce tumor cell death [10, 11]. The discovery of cuproptosis has sparked interest among researchers exploring the relationship between cuproptosis and tumors. Since recent developments in this field of study are primarily focused on gene expression, one area of research involves investigating the expression levels of cuproptosis-related genes and their role in tumorigenesis, tumor treatment, and drug resistance to clarify the role of cuproptosis in these processes [12, 13]. Due to the unmet clinical need to treat cancer, new approaches are required. Another focus of the study is developing strategies for effective cancer treatment based on cuproptosis. Researchers have found that high levels of aerobic respiration and mitochondrial metabolism can sensitize tumor cells to cuproptosis, thereby enhancing their therapeutic effect [7]. The targeted delivery of Cu or Cu ionophores can be used to specifically kill cancer cells. In-depth research on cuproptosis in cancer will provide a scientific basis for developing clinical strategies aimed at targeting cuproptosis to improve tumor therapy. In this review, we synthesized current understanding on copper metabolism and the molecular mechanisms underlying cuproptosis. We also explored the potential correlations between the expression of cuproptosis-associated genes across different tumor types and patient prognosis, with the goal of offering innovative insights into cuproptosis-based tumor therapy. Additionally, we outlined contemporary strategies for targeting cuproptosis in cancer treatment, including the use of Cu ionophores and nanoparticlebased precision delivery systems. Furthermore, we discussed the potential application of targeting cuproptosis to overcome resistance to chemotherapy in tumors. Our aim is to provide a new perspective for targeting cuproptosis-related tumor therapy. Cu metabolism Regulation of Cu levels in the body is crucial for maintaining normal cellular processes. Cu serves as a cofactor for numerous enzymes and is vital in various biochemical reactions. Cu is mainly obtained from diet, with visceral meat and shellfish being the richest sources. Once ingested, Cu ions (...truncated)