Cell Reports
Volume 27, Issue 3, 16 April 2019, Pages 820-834.e9
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Article
Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate

https://doi.org/10.1016/j.celrep.2019.03.058Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

MDM2
Krebs cycle
glycolysis
mitochondrial fragmentation
regulated cell death
parthanatos
cancer metabolism

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