Cuproptosis: unveiling a new frontier in cancer biology and therapeutics

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Abstract

Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types.

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

Roel Nusse, Hans Clevers (2017)

The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.

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Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter Tsvetkov, Shannon Coy, Boryana Petrova … (2022)

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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Author and article information

Contributors

Hai Zhao: yidao@qdu.edu.cn

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 1 May 2024

Publication date PMC-release: 1 May 2024

Publication date Collection: 2024

Volume: 22

Electronic Location Identifier: 249

Affiliations

[1 ]Department of Emergency, the Affiliated Hospital of Qingdao University, ( https://ror.org/026e9yy16) No. 16 Jiangsu Road, Qingdao, 266005 Shandong China

[2 ]Department of Neurosurgery, 3201 Hospital of Xi’an Jiaotong University Health Science Center, ( https://ror.org/017zhmm22) Hanzhong, 723000 Shaanxi China

[3 ]Department of Neurosurgery, the Affiliated Hospital of Qingdao University, ( https://ror.org/026e9yy16) No. 16 Jiangsu Road, Qingdao, 266005 Shandong China

Article

Publisher ID: 1625

DOI: 10.1186/s12964-024-01625-7

PMC ID: 11064406

PubMed ID: 38693584

SO-VID: 0af89aa1-e688-455d-81ce-7e0339ce96c9

License:

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

Date received : 26 February 2024

Date accepted : 21 April 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100007129, Natural Science Foundation of Shandong Province;

Award ID: ZR2022QH372

Award Recipient : Jianpeng Wang Hai Zhao

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ScienceOpen disciplines: Cell biology

Keywords: cuproptosis,copper,immunotherapy,targetted therapy,copper homeostasis,mitochondria

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ScienceOpen disciplines: Cell biology

Keywords: cuproptosis, copper, immunotherapy, targetted therapy, copper homeostasis, mitochondria

Cuproptosis: unveiling a new frontier in cancer biology and therapeutics

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GLUT4 biology

Most cited references 222

Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

Copper induces cell death by targeting lipoylated TCA cycle proteins

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