title: Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner.
abstract: 2-Oxoglutarate dehydrogenase (OGDH) of the tricarboxylic acid (TCA) cycle is often implied to be inactive in cancer, but this was not experimentally tested. We addressed the question through specific inhibition of OGDH by succinyl phosphonate (SP). SP action on different cancer cells was investigated using indicators of cellular viability and reactive oxygen species (ROS), metabolic profiling and transcriptomics. Relative sensitivity of various cancer cells to SP changed with increasing SP exposure and could differ in the ATP- and NAD(P)H-based assays. Glioblastoma responses to SP revealed metabolic sub-types increasing or decreasing cellular ATP/NAD(P)H ratio under OGDH inhibition. Cancer cell homeostasis was perturbed also when viability indicators were SP-resistant, e.g. in U87 and N2A cells. The transcriptomics database analysis showed that the SP-sensitive cells, such as A549 and T98G, exhibit the lowest expression of OGDH compared to other TCA cycle enzymes, associated with higher expression of affiliated pathways utilizing 2-oxoglutarate. Metabolic profiling confirmed the dependence of cellular SP reactivity on cell-specific expression of the pathways. Thus, oxidative decarboxylation of 2-oxoglutarate is significant for the interdependent homeostasis of NAD(P)H, ATP, ROS and key metabolites in various cancer cells. Assessment of cell-specific responses to OGDH inhibition is of diagnostic value for anticancer strategies.
authors.affiliation: Belozersky Institute and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.|Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Victoria I
authors.initials: VI
authors.lastname: Bunik
authors.affiliation: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Garik
authors.initials: G
authors.lastname: Mkrtchyan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
authors.forename: Aneta
authors.initials: A
authors.lastname: Grabarska
authors.affiliation: Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Oppermann
authors.affiliation: Max-Planck-Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Daloso
authors.affiliation: Max-Planck Partner Group at The Departamento de Biologia Vegetal, Universida de Federal de Viçosa, Viçosa, Brazil.
authors.forename: Wagner L
authors.initials: WL
authors.lastname: Araujo
authors.affiliation: Department of Medical Biology, Institute of Agricultural Medicine, Lublin, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Juszczak
authors.affiliation: Department of Medical Biology, Institute of Agricultural Medicine, Lublin, Poland.|Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Skłodowska University, Lublin, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Rzeski
authors.affiliation: GIGA-Neurosciences, University of Liege, Liege, Belgium.
authors.forename: Lucien
authors.initials: L
authors.lastname: Bettendorff
authors.affiliation: Max-Planck-Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
authors.forename: Alisdair R
authors.initials: AR
authors.lastname: Fernie
authors.affiliation: Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Meixensberger
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.|Department of Otolaryngology, MSW Hospital, Lublin, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Stepulak
authors.affiliation: Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Gaunitz
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000378:metabolism*; D063065:Organophosphonates / Q000494:pharmacology; D013386:Succinates / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D063065:Organophosphonates; D013386:Succinates; C099145:succinyl phosphonate; D007655:Ketoglutarate Dehydrogenase Complex
keywords: 2-oxoglutarate dehydrogenase; amino acid transamination; cystine/glutamate antiporter; glioblastoma; succinyl phosphonate