Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate

Valentina Sica, Jose Manuel Bravo-San Pedro, Valentina Izzo, Jonathan Pol, Sandra Pierredon, David Enot, Sylvère Durand, Noélie Bossut, Alexis Chery, Sylvie Souquere, Gerard Pierron, Evangelia Vartholomaiou, Naoufal Zamzami, Thierry Soussi, Allan Sauvat, Laura Mondragón, Oliver Kepp, Lorenzo Galluzzi, Jean Claude Martinou, Holger Hess-StumppKarl Ziegelbauer, Guido Kroemer, Maria Chiara Maiuri

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    32 Citations (Scopus)

    Résumé

    Inhibition of oxidative phosphorylation (OXPHOS) by 1-cyclopropyl-4-(4-[(5-methyl-3-(3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl]pyridin-2-yl)piperazine (BAY87-2243, abbreviated as B87), a complex I inhibitor, fails to kill human cancer cells in vitro. Driven by this consideration, we attempted to identify agents that engage in synthetically lethal interactions with B87. Here, we report that dimethyl α-ketoglutarate (DMKG), a cell-permeable precursor of α-ketoglutarate that lacks toxicity on its own, kills cancer cells when combined with B87 or other inhibitors of OXPHOS. DMKG improved the antineoplastic effect of B87, both in vitro and in vivo. This combination caused MDM2-dependent, tumor suppressor protein p53 (TP53)-independent transcriptional reprogramming and alternative exon usage affecting multiple glycolytic enzymes, completely blocking glycolysis. Simultaneous inhibition of OXPHOS and glycolysis provoked a bioenergetic catastrophe culminating in the activation of a cell death program that involved disruption of the mitochondrial network and activation of PARP1, AIFM1, and APEX1. These results unveil a metabolic liability of human cancer cells that may be harnessed for the development of therapeutic regimens.

    langue originaleAnglais
    Pages (de - à)820-834.e9
    journalCell Reports
    Volume27
    Numéro de publication3
    Les DOIs
    étatPublié - 16 avr. 2019

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