Oncotarget

Research Papers:

Inhibition of mitochondrial 2-oxoglutarate dehydrogenase impairs viability of cancer cells in a cell-specific metabolism-dependent manner

Victoria I. Bunik _, Garik Mkrtchyan, Aneta Grabarska, Henry Oppermann, Danilo Daloso, Wagner L. Araujo, Malgorzata Juszczak, Wojciech Rzeski, Lucien Bettendorff, Alisdair R. Fernie, Jürgen Meixensberger, Andrzej Stepulak and Frank Gaunitz

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Oncotarget. 2016; 7:26400-26421. https://doi.org/10.18632/oncotarget.8387

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Abstract

Victoria I. Bunik1,2, Garik Mkrtchyan2, Aneta Grabarska3, Henry Oppermann4, Danilo Daloso5, Wagner L. Araujo6, Malgorzata Juszczak7, Wojciech Rzeski7,8, Lucien Bettendorff9, Alisdair R. Fernie5, Jürgen Meixensberger4, Andrzej Stepulak3,10, Frank Gaunitz4

1Belozersky Institute and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia

2Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia

3Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland

4Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany

5Max-Planck-Institute of Molecular Plant Physiology, Potsdam-Golm, Germany

6Max-Planck Partner Group at The Departamento de Biologia Vegetal, Universida de Federal de Viçosa, Viçosa, Brazil

7Department of Medical Biology, Institute of Agricultural Medicine, Lublin, Poland

8Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Skłodowska University, Lublin, Poland

9GIGA-Neurosciences, University of Liege, Liege, Belgium

10Department of Otolaryngology, MSW Hospital, Lublin, Poland

Correspondence to:

Victoria I. Bunik, email: [email protected]

Keywords: amino acid transamination, cystine/glutamate antiporter, glioblastoma, 2-oxoglutarate dehydrogenase, succinyl phosphonate

Received: September 12, 2015     Accepted: March 11, 2016     Published: March 26, 2016

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.


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