Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate
| العنوان: | Lethal Poisoning of Cancer Cells by Respiratory Chain Inhibition plus Dimethyl α-Ketoglutarate |
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| المؤلفون: | Sica V., Bravo-San Pedro J. M., Izzo V., Pol J., Pierredon S., Enot D., Durand S., Bossut N., Chery A., Souquere S., Pierron G., Vartholomaiou E., Zamzami N., Soussi T., Sauvat A., Mondragon L., Kepp O., Galluzzi L., Martinou J. -C., Hess-Stumpp H., Ziegelbauer K., Kroemer G., Maiuri M. C. |
| المساهمون: | Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Institut Gustave Roussy (IGR), University of Geneva [Switzerland], Rétrovirus endogènes et éléments rétroïdes des eucaryotes supérieurs (UMR 9196), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Cancer Center Karolinska [Karolinska Institutet] (CCK), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], Yale University School of Medicine, Bayer Pharma AG [Berlin], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Gestionnaire, Hal Sorbonne Université, Université de Genève = University of Geneva (UNIGE), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Yale School of Medicine [New Haven, Connecticut] (YSM), Sica, V., Bravo-San Pedro, J. M., Izzo, V., Pol, J., Pierredon, S., Enot, D., Durand, S., Bossut, N., Chery, A., Souquere, S., Pierron, G., Vartholomaiou, E., Zamzami, N., Soussi, T., Sauvat, A., Mondragon, L., Kepp, O., Galluzzi, L., Martinou, J. -C., Hess-Stumpp, H., Ziegelbauer, K., Kroemer, G., Maiuri, M. C. |
| المصدر: | Cell Reports Cell Reports, Elsevier Inc, 2019, 27 (3), pp.820-834.e9. ⟨10.1016/j.celrep.2019.03.058⟩ Cell Reports, Vol 27, Iss 3, Pp 820-834.e9 (2019) Cell Reports, 2019, 27 (3), pp.820-834.e9. ⟨10.1016/j.celrep.2019.03.058⟩ |
| بيانات النشر: | HAL CCSD, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Glycolysi, parthanato, mitochondrial fragmentation, Poly (ADP-Ribose) Polymerase-1, Mice, Nude, cancer metabolism, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Oxadiazole, Oxidative Phosphorylation, Ketoglutaric Acid, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, MDM2, parthanatos, Cell Line, Tumor, Animals, Humans, RNA, Small Interfering, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, lcsh:QH301-705.5, Oxadiazoles, Electron Transport Complex I, Animal, regulated cell death, Apoptosi, Apoptosis Inducing Factor, Proto-Oncogene Proteins c-mdm2, glycolysis, Isocitrate Dehydrogenase, Mitochondria, lcsh:Biology (General), Pyrazole, Ketoglutaric Acids, Pyrazoles, Female, RNA Interference, Tumor Suppressor Protein p53, Krebs cycle, Human |
| الوصف: | 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 |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2211-1247 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::9237f157179cf62166902e847f70abc7 https://hal.sorbonne-universite.fr/hal-02317988 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.pmid.dedup....9237f157179cf62166902e847f70abc7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22111247 |
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