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      The crosstalk between copper-induced oxidative stress and cuproptosis: a novel potential anticancer paradigm

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          Abstract

          Copper is a crucial trace element that plays a role in various pathophysiological processes in the human body. Copper also acts as a transition metal involved in redox reactions, contributing to the generation of reactive oxygen species (ROS). Under prolonged and increased ROS levels, oxidative stress occurs, which has been implicated in different types of regulated cell death. The recent discovery of cuproptosis, a copper-dependent regulated cell death pathway that is distinct from other known regulated cell death forms, has raised interest to researchers in the field of cancer therapy. Herein, the present work aims to outline the current understanding of cuproptosis, with an emphasis on its anticancer activities through the interplay with copper-induced oxidative stress, thereby providing new ideas for therapeutic approaches targeting modes of cell death in the future.

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          Most cited references126

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          Hallmarks of Cancer: New Dimensions

          The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
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            Copper induces cell death by targeting lipoylated TCA cycle proteins

            Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al . investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.
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              The molecular machinery of regulated cell death

              Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.
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                Author and article information

                Contributors
                itlee0128@tmu.edu.tw
                Journal
                Cell Commun Signal
                Cell Commun Signal
                Cell Communication and Signaling : CCS
                BioMed Central (London )
                1478-811X
                5 July 2024
                5 July 2024
                2024
                : 22
                : 353
                Affiliations
                [1 ]Faculty of Dentistry, Nguyen Tat Thanh University, ( https://ror.org/04r9s1v23) Ho Chi Minh City, 700000 Vietnam
                [2 ]School of Dentistry, College of Oral Medicine, Taipei Medical University, ( https://ror.org/05031qk94) Taipei, 110301 Taiwan
                [3 ]School of Food Safety, College of Nutrition, Taipei Medical University, ( https://ror.org/05031qk94) Taipei, 110301 Taiwan
                [4 ]Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, ( https://ror.org/05bqach95) Taipei, 100233 Taiwan
                Article
                1726
                10.1186/s12964-024-01726-3
                11225285
                38970072
                50456139-1d13-4565-a8c8-c6a4051b1fcc
                © 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/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 11 April 2024
                : 25 June 2024
                Funding
                Funded by: College of Oral Medicine, Taipei Medical University, Taiwan
                Award ID: TMUCOM202405
                Categories
                Review
                Custom metadata
                © BioMed Central Ltd., part of Springer Nature 2024

                Cell biology
                copper,cuproptosis,reactive oxygen species,oxidative stress
                Cell biology
                copper, cuproptosis, reactive oxygen species, oxidative stress

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