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

• Published in: Cell reports (Cambridge) 2019-04, Vol.27 (3), p.820-834.e9
• Main Authors: Sica, Valentina, Bravo-San Pedro, Jose Manuel, Izzo, Valentina, Pol, Jonathan, Pierredon, Sandra, Enot, David, Durand, Sylvère, Bossut, Noélie, Chery, Alexis, Souquere, Sylvie, Pierron, Gerard, Vartholomaiou, Evangelia, Zamzami, Naoufal, Soussi, Thierry, Sauvat, Allan, Mondragón, Laura, Kepp, Oliver, Galluzzi, Lorenzo, Martinou, Jean-Claude, Hess-Stumpp, Holger, Ziegelbauer, Karl, Kroemer, Guido, Maiuri, Maria Chiara
• Format: Article
• Language: English
• Subjects: Cancer; cancer metabolism; Cellular Biology; glycolysis; Krebs cycle; Life Sciences; MDM2; Medicin och hälsovetenskap; mitochondrial fragmentation; parthanatos; regulated cell death
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.03.058

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. [Display omitted] •The respiratory chain complex I inhibitor BAY87-2243 (B87) fails to kill cancer cells•B87 combined with dimethyl alpha-ketoglutarate (DMKG) causes cancer cell death•The lethal action of B87 + DMKG requires MDM2 but not TP53•B87 plus DMKG shuts off glycolysis through MDM2-dependent transcriptional reprogramming Sica et al. show that respiratory chain inhibition 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) becomes lethal for cancer cells when glycolysis is simultaneously suppressed. When combined with B87, dimethyl α-ketoglutarate acquires the capacity to suppress glycolysis, thus lethally poisoning bioenergetics metabolism. This therapeutic combination effect relies on transcriptional reprogramming that can be reverted by pharmacological inhibition of MDM2.