Targeting cuproplasia and cuproptosis in cancer

• Published in: Nature reviews. Clinical oncology 2024-05, Vol.21 (5), p.370-388
• Main Authors: Tang, Daolin, Kroemer, Guido, Kang, Rui
• Format: Article
• Language: English
• Subjects: 692/308/53/2422; 692/308/575; 692/699/67/1857; 692/699/67/2327; 692/700/565/1436; Autophagy; Cancer therapies; Cell death; Cell growth; Copper; Copper - metabolism; Ferroptosis; Homeostasis; Humans; Hyperplasia; Immunomodulation; Medicine; Medicine & Public Health; Metabolism; Metaplasia; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oncology; Redox properties; Review Article; Trace elements; Tumorigenesis
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-024-00876-0

Copper, an essential trace element that exists in oxidized and reduced forms, has pivotal roles in a variety of biological processes, including redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy and immune modulation; maintaining copper homeostasis is crucial as both its deficiency and its excess are deleterious. Dysregulated copper metabolism has a dual role in tumorigenesis and cancer therapy. Specifically, cuproplasia describes copper-dependent cell growth and proliferation, including hyperplasia, metaplasia and neoplasia, whereas cuproptosis refers to a mitochondrial pathway of cell death triggered by excessive copper exposure and subsequent proteotoxic stress (although complex interactions between cuproptosis and other cell death mechanisms, such as ferroptosis, are likely and remain enigmatic). In this Review, we summarize advances in our understanding of copper metabolism, the molecular machineries underlying cuproplasia and cuproptosis, and their potential targeting for cancer therapy. These new findings advance the rapidly expanding field of translational cancer research focused on metal compounds. Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer. Key points Copper is an essential trace element that has crucial roles in both normal physiological processes and pathological processes, including cancer. Cuproplasia is a term used to describe the role of copper in promoting cell proliferation and growth. Cuproptosis is a type of mitochondrial cell death driven by proteotoxic stress associated with protein lipoylation and degradation of Fe–S cluster proteins. Ferredoxin 1 has a key role in cuproptosis by reducing Cu(II) to Cu(I) in mitochondria, facilitating excessive protein lipoylation and subsequent aggregation related to mitochondrial respiration. Cuproplasia-related and/or cuproptosis-related genes have potential pro