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Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells

Abstract : The clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than met-formin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunc-tion and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting.
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Submitted on : Tuesday, November 27, 2018 - 9:30:56 AM
Last modification on : Thursday, January 21, 2021 - 11:47:52 AM


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Sebastian Müller, Antoine Versini, Fabien Sindikubwabo, Guillaume Belthier, Supaporn Niyomchon, et al.. Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells. PLoS ONE, Public Library of Science, 2018, 13 (11), pp.e0206764. ⟨10.1371/journal.pone.0206764⟩. ⟨hal-01935757⟩



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