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

Bunik, Victoria I.; Mkrtchyan, Garik; Grabarska, Aneta; Oppermann, Henry; Daloso, Danilo de Menezes; Araújo, Wagner L.; Juszczak, Małgorzata; Rzeski, Wojciech; Bettendorff, Lucien; Fernie, Alisdair R.; Meixensberger, Jürgen; Stepulak, Andrzej; Gaunitz, Frank

doi:10.18632/oncotarget.8387

Cited by 35 publications

(36 citation statements)

References 82 publications

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“…2OG mimetic tool compounds have been shown to have antiproliferative activity in a small set of cancer cell lines, albeit at high doses (mM) (55), making it difficult to extend these studies to animal models. Nevertheless, our observations suggest that further development of these or similar compounds may have potential therapeutic value if toxicity that may be caused by OGDH inhibition can be tolerated due to the reported association between its reduced activity and neurodegenerative disorders (56).…”

Section: Discussionmentioning

confidence: 99%

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Ilić

Birsoy

Aguirre

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale lossof-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.

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Section: Discussionmentioning

confidence: 99%

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Ilić

Birsoy

Aguirre

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The importance of interplay between metabolism of glucose and glutamate in cancer cells has been shown upon inhibition of the 2-oxoglutarate dehydrogenase complex reaction at the pathways intercept [208]. Investigation of compensatory metabolic pathways and signaling functions of their intermediates may help to improve the efficacy of cancer therapies [200,207,208].…”

Section: Medical Significance Of Gdhmentioning

confidence: 99%

“…Investigation of compensatory metabolic pathways and signaling functions of their intermediates may help to improve the efficacy of cancer therapies [200,207,208]. …”

Section: Medical Significance Of Gdhmentioning

confidence: 99%

Multiple Forms of Glutamate Dehydrogenase in Animals: Structural Determinants and Physiological Implications

Bunik

Artiukhov

Aleshin

et al. 2016

Biology

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Glutamate dehydrogenase (GDH) of animal cells is usually considered to be a mitochondrial enzyme. However, this enzyme has recently been reported to be also present in nucleus, endoplasmic reticulum and lysosomes. These extramitochondrial localizations are associated with moonlighting functions of GDH, which include acting as a serine protease or an ATP-dependent tubulin-binding protein. Here, we review the published data on kinetics and localization of multiple forms of animal GDH taking into account the splice variants, post-translational modifications and GDH isoenzymes, found in humans and apes. The kinetic properties of human GLUD1 and GLUD2 isoenzymes are shown to be similar to those published for GDH1 and GDH2 from bovine brain. Increased functional diversity and specific regulation of GDH isoforms due to alternative splicing and post-translational modifications are also considered. In particular, these structural differences may affect the well-known regulation of GDH by nucleotides which is related to recent identification of thiamine derivatives as novel GDH modulators. The thiamine-dependent regulation of GDH is in good agreement with the fact that the non-coenzyme forms of thiamine, i.e., thiamine triphosphate and its adenylated form are generated in response to amino acid and carbon starvation.

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“…While OGDH has been reported to contribute to fumarate accumulation and optimal growth of FH-deficient cells (Sullivan et al, 2013), we wanted to determine its role in a broader array of cancer cell lines. A recent report demonstrated differential sensitivity of several cell lines to the phosphonate analog of alpha-ketoglutarate and OGDH inhibitor, succinyl phosphonate (SP) (Bunik et al, 2016). We used highly validated small hairpin RNA (shRNA) tools in an expanded panel of cancer cell lines and identified a range of cellular dependence on OGDH, with some cell lines being completely OGDH independent.…”

Section: Introductionmentioning

confidence: 99%

Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH

et al. 2016

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Although aberrant metabolism in tumors has been well described, the identification of cancer subsets with particular metabolic vulnerabilities has remained challenging. Here, we conducted an siRNA screen focusing on enzymes involved in the tricarboxylic acid (TCA) cycle and uncovered a striking range of cancer cell dependencies on OGDH, the E1 subunit of the alpha-ketoglutarate dehydrogenase complex. Using an integrative metabolomics approach, we identified differential aspartate utilization, via the malate-aspartate shuttle, as a predictor of whether OGDH is required for proliferation in 3D culture assays and for the growth of xenograft tumors. These findings highlight an anaplerotic role of aspartate and, more broadly, suggest that differential nutrient utilization patterns can identify subsets of cancers with distinct metabolic dependencies for potential pharmacological intervention.

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

Cited by 35 publications

References 82 publications

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Multiple Forms of Glutamate Dehydrogenase in Animals: Structural Determinants and Physiological Implications

Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH

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