[en] 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 SPresistant,
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 cellspecific
responses to OGDH inhibition is of diagnostic value for anticancer strategies.
Research Center/Unit :
Giga-Neurosciences - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bunik, Victoria; Lomonosov Moscow State University - MSU > Belozersky Institute and Bioinformatics & Faculty of Bioengineering and Bioinformatics
Mkrtchyan, Garait; Lomonosov Moscow State University - MSU > Faculty of Bioengineering and Bioinformatics
Grabarska, Aneta; Medical University, Lublin, Poland > Department of Biochemistry and Molecular Biology
Oppermann, Henry; University Hospital Leipzig > Department of Neurosurgery,
Daloso, Danilo; ax-Planck-Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
Araujo, Wagner L.; Max-Planck Partner Group at the Departamento de Biologia Vegetal, Universida de Federal de Viçosa, Viçosa, Minas Gerais, Brazil
Juszczak, Malgorzata; Medical University, Lublin, Poland > Department of Biochemistry and Molecular Biology
Rzeski, Wojciech; Institute of Agricultural Medicine, Lublin, Poland & Maria Curie-Skłodowska University, Lublin, Poland > Department of Medical Biology
Bettendorff, Lucien ; Université de Liège > Département des sciences biomédicales et précliniques > Biochimie et physiologie humaine et pathologique
Fernie, Alisdair R.; ax-Planck-Institute of Molecular Plant Physiology, Potsdam-Golm, Germany
Meixensberger, Jürgen; University Hospital Leipzig > Department of Neurosurgery
Stepulak, Andrzej; Medical University, Lublin, Poland & Department of Otolaryngology of MSW Hospital, > Department of Biochemistry and Molecular Biology
Gaunitz, Frank; University Hospital Leipzig, Leipzig, Germany > Department of Neurosurgery
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