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Oncotarget. 2016 May 3;7(18):26400-21. doi: 10.18632/oncotarget.8387.

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

Author information

1
Belozersky Institute and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
2
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
3
Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
4
Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.
5
Max-Planck-Institute of Molecular Plant Physiology, Potsdam-Golm, Germany.
6
Max-Planck Partner Group at The Departamento de Biologia Vegetal, Universida de Federal de Viçosa, Viçosa, Brazil.
7
Department of Medical Biology, Institute of Agricultural Medicine, Lublin, Poland.
8
Department of Virology and Immunology, Institute of Microbiology and Biotechnology, Maria Curie-Skłodowska University, Lublin, Poland.
9
GIGA-Neurosciences, University of Liege, Liege, Belgium.
10
Department of Otolaryngology, MSW Hospital, Lublin, Poland.

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.

KEYWORDS:

2-oxoglutarate dehydrogenase; amino acid transamination; cystine/glutamate antiporter; glioblastoma; succinyl phosphonate

PMID:
27027236
PMCID:
PMC5041988
DOI:
10.18632/oncotarget.8387
[Indexed for MEDLINE]
Free PMC Article

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