Connecting copper and cancer: from transition metal signalling to metalloplasia

Ge, Eva; Bush, Ashley I.; Casini, Angela; Cobine, Paul A.; Cross, Justin R.; DeNicola, Gina M.; Dou, Q. Ping; Franz, Katherine J.; Gohil, Vishal M.; Gupta, Sanjeev; Kaler, Stephen G.; Lutsenko, Svetlana; Mittal, Vivek; Petris, Michael J.; Polishchuk, Roman; Ralle, Martina; Schilsky, Michael L.; Tonks, Nicholas K.; Vahdat, Linda T.; Aelst, Linda Van; Xi, Dan; Yuan, Peng; Brady, Donita C.; Chang, Christopher J.

doi:10.1038/s41568-021-00417-2

Cited by 704 publications

(680 citation statements)

References 163 publications

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“…As an essential cofactor, copper homeostasis is critical for various physiological processes. Dysregulation of intracellular copper bioavailability can induce oxidative stress and cytotoxicity 2 . In the animal kingdom, from prokaryotes to eukaryotes, copper homeostasis is finely regulated mainly by preventing excessive accumulation of copper ions in cells which threats cell survival.…”

mentioning

confidence: 99%

Cuproptosis: lipoylated TCA cycle proteins-mediated novel cell death pathway

Cai

2022

Sig Transduct Target Ther

174

113

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confidence: 99%

Cuproptosis: lipoylated TCA cycle proteins-mediated novel cell death pathway

Cai

2022

Sig Transduct Target Ther

174

113

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“…When we refer to Cu-binding compounds, different classes of Cu ligands are included such as Cu chelators and Cu ionophores. Cu ionophores differ from Cu chelators for their mechanism of action as reported elsewhere (Oliveri, 2020;Ge et al, 2021). In particular, Cu chelators inhibit cuproplasia, a Cudependent cellular proliferation, whereas Cu ionophores induce cuproptosis (Figure 1).…”

Section: Copper Ionophoresmentioning

confidence: 75%

“…This hypothesis is, for example, supported by the enhanced incidence of hepatocarcinoma in Wilson's disease patients, the correlation between the stage and Cu levels in colorectal and breast cancer, the link between Cu exposure, pancreatic and prostate cancer (Gupta et al, 1993;Sharma et al, 1994;Ishida et al, 2013;Gunjan et al, 2017;Vella et al, 2017). Moreover, some mechanisms, involved in Cu-dependent growth and progression of tumors, have been recently found and summarized elsewhere (Lelièvre et al, 2020;Ge et al, 2021;Ruiz et al, 2021). Cu is also able to promote angiogenesis that is essential for tumor progression and metastasis.…”

Section: Introductionmentioning

confidence: 90%

“…Many different classes of Cu ionophores have been pursued as anticancer agents to promote cuproptosis, including dithiocarbamates, bis(thiosemicarbazone) ligands, 8hydroxyquinolines (HQs), flavones, etc (Denoyer et al, 2015;Hunsaker and Franz, 2019;Lelièvre et al, 2020;Li, 2020;Ge et al, 2021). The structure of the Cu ionophores mentioned in this paper is reported in Table 1.…”

Section: Copper Ionophoresmentioning

confidence: 99%

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Selective Targeting of Cancer Cells by Copper Ionophores: An Overview

Oliveri

2022

Front. Mol. Biosci.

228

183

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Conventional cancer therapies suffer from severe off-target effects because most of them target critical facets of cells that are generally shared by all rapidly proliferating cells. The development of new therapeutic agents should aim to increase selectivity and therefore reduce side effects. In addition, these agents should overcome cancer cell resistance and target cancer stem cells. Some copper ionophores have shown promise in this direction thanks to an intrinsic selectivity in preferentially inducing cuproptosis of cancer cells compared to normal cells. Here, Cu ionophores are discussed with a focus on selectivity towards cancer cells and on the mechanisms responsible for this selectivity. The proposed strategies, to further improve the targeting of cancer cells by copper ionophores, are also reported.

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“…Thus, CD44 can be more generally defined as a regulator of cell plasticity. Copper has previously been shown to play a role in immune defense and cancer 37,38 . For example, copper has been proposed to promote the production of reactive oxygen species as a defense mechanism against bacteria 39 .…”

Section: Discussionmentioning

confidence: 99%

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

Solier

Müller

Cañeque

et al. 2022

Preprint

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Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral infections (SARS-CoV-2), improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

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Connecting copper and cancer: from transition metal signalling to metalloplasia

Cited by 704 publications

References 163 publications

Cuproptosis: lipoylated TCA cycle proteins-mediated novel cell death pathway

Cuproptosis: lipoylated TCA cycle proteins-mediated novel cell death pathway

Selective Targeting of Cancer Cells by Copper Ionophores: An Overview

Discovery of a druggable copper-signaling pathway that drives cell plasticity and inflammation

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