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-Stumpp,
Karl Ziegelbauer,
Guido Kroemer,
Maria Chiara Maiuri
Affiliations
Valentina Sica
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Jose Manuel Bravo-San Pedro
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Valentina Izzo
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Jonathan Pol
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Sandra Pierredon
Department of Cell Biology, University of Geneva, 1211 Geneva, Switzerland
David Enot
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Sylvère Durand
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Noélie Bossut
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Alexis Chery
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Sylvie Souquere
CNRS-UMR-9196, Institut Gustave Roussy, 94805 Villejuif, France
Gerard Pierron
CNRS-UMR-9196, Institut Gustave Roussy, 94805 Villejuif, France
Evangelia Vartholomaiou
Department of Cell Biology, University of Geneva, 1211 Geneva, Switzerland
Naoufal Zamzami
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Thierry Soussi
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, 17176 Stockholm, Sweden
Allan Sauvat
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Laura Mondragón
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Oliver Kepp
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France
Lorenzo Galluzzi
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06510, USA
Jean-Claude Martinou
Department of Cell Biology, University of Geneva, 1211 Geneva, Switzerland
Holger Hess-Stumpp
Global Drug Discovery, Bayer Pharma AG, 13353 Berlin, Germany
Karl Ziegelbauer
Research & Development, Pharmaceuticals, Bayer AG, 42117 Wuppertal, Germany
Guido Kroemer
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France; Karolinska Institute, Department of Women’s and Children’s Health, Karolinska University Hospital, 17176 Stockholm, Sweden; Corresponding author
Maria Chiara Maiuri
Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Equipe 11 labellisée par la Ligue contre le Cancer, 75006 Paris, France; Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 Villejuif, France; Corresponding author
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. : 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. Keywords: MDM2, Krebs cycle, glycolysis, mitochondrial fragmentation, regulated cell death, parthanatos, cancer metabolism
