TY - JOUR
T1 - Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate
AU - Sica, Valentina
AU - Bravo-San Pedro, Jose Manuel
AU - Izzo, Valentina
AU - Pol, Jonathan
AU - Pierredon, Sandra
AU - Enot, David
AU - Durand, Sylvère
AU - Bossut, Noélie
AU - Chery, Alexis
AU - Souquere, Sylvie
AU - Pierron, Gerard
AU - Vartholomaiou, Evangelia
AU - Zamzami, Naoufal
AU - Soussi, Thierry
AU - Sauvat, Allan
AU - Mondragón, Laura
AU - Kepp, Oliver
AU - Galluzzi, Lorenzo
AU - Martinou, Jean Claude
AU - Hess-Stumpp, Holger
AU - Ziegelbauer, Karl
AU - Kroemer, Guido
AU - Maiuri, Maria Chiara
N1 - Publisher Copyright:
© 2019 The Author(s)
PY - 2019/4/16
Y1 - 2019/4/16
N2 - 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.
AB - 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.
KW - cancer metabolism
KW - glycolysis
KW - Krebs cycle
KW - MDM2
KW - mitochondrial fragmentation
KW - parthanatos
KW - regulated cell death
UR - http://www.scopus.com/inward/record.url?scp=85064147853&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.03.058
DO - 10.1016/j.celrep.2019.03.058
M3 - Article
C2 - 30995479
AN - SCOPUS:85064147853
SN - 2211-1247
VL - 27
SP - 820-834.e9
JO - Cell Reports
JF - Cell Reports
IS - 3
ER -
