Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism

Lussey-Lepoutre, Charlotte; Hollinshead, Kate E.R.; Ludwig, Christian; Menara, Mélanie; Morin, Aurélie; Castro-Vega, Luis-Jaime; Parker, Seth J.; Janin, Maxime; Martinelli, Cosimo; Ottolenghi, Chris; Metallo, Christian M.; Gimenez-Roqueplo, Anne-Paule; Favier, Judith; Tennant, Daniel A.

doi:10.1038/ncomms9784

Cited by 190 publications

(172 citation statements)

References 39 publications

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“…GOT2 converts oxaloacetate into aspartate by transamination, with the consequent conversion of glutamate to a-ketoglutarate. In SDH-deficient cells, glutamine and glutamate are used to provide metabolic intermediates to the truncated Krebs cycle, after conversion to a-ketoglutarate by GOT2 or GLUD1 enzymes (36,37). It has been recently described that lysine acetylation of GOT2 enhances the protein association between GOT2 and MDH2, stimulating the malate shuttle activity and thus promoting pancreatic cell proliferation and tumor growth in vivo (38).…”

Section: Discussionmentioning

confidence: 99%

Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

Remacha

Comino-Méndez

Richter

et al. 2017

Clinical Cancer Research

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Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes.Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases.Results: One of the 11 tumors was found to carry a known cancer-predisposing somatic mutation in IDH1. A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knockdown HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered a-ketoglutarate/ isocitrate ratio.Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol. Clin Cancer Res; 23(20); 6315-24. Ó2017 AACR.

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Section: Discussionmentioning

confidence: 99%

Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

Remacha

Comino-Méndez

Richter

et al. 2017

Clinical Cancer Research

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“…These mutations often result in the production of excess "oncometabolites" that promote activation of proliferative transcription factors and regulate DNA methylation (6). Tracer studies show that SDH-null cells produce citrate predominantly through reductive carboxylation of Gln and accumulate Gln-derived succinate, a product inhibitor of the ␣-KG-dependent dioxygenases, while relying on PC for anaplerosis and synthesis of aspartate to support nucleotide biosynthesis required for proliferation (59,86,87). Likewise, IDH1 mutant cells increased conversion of [ 13 C 1 -2]Glc to PC-derived [ 13 C 1 -3]Glu, which implicates the importance of PC anaplerosis for proliferation of these cells (88).…”

Section: Applications Of Sirm In Drug Developmentmentioning

confidence: 99%

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

Bruntz

Lane

Higashi

et al. 2017

Journal of Biological Chemistry

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Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.Metabolism is the collection of predominantly enzyme-catalyzed biochemical transformations that meet the growth and survival demands of an organism. For nearly a century, scientists have documented profound metabolic changes that occur in tumors (1, 2). One of the earliest insights into cancer metabolism came when Otto Warburg noted increased uptake and fermentation of glucose (Glc) 3 to lactate in tumors relative to surrounding tissue, even in the presence of ample oxygen (2). Clinical cancer diagnosis exploits this "Warburg effect" by measuring uptake of the Glc analogue 18 F-deoxyglucose using positron emission tomography (PET), as the metabolic demands of differentiated, non-proliferating tissues generally require far less Glc than tumors (3).Oncoproteins and tumor suppressors are well-established regulators of metabolism, and mutations or dysregulated expression can lead to the altered metabolic phenotypes observed in many cancers (4, 5). Inactivating mutations in enzymes such as fumarate hydratase (FH) or succinate dehydrogenase (SDH) induce pathophysiological accumulation of substrates that inhibit other critical enzyme functions, whereas less common gain-of-function mutations such as in isocitrate dehydrogenases (IDH) produce metabolites that directly deregulate cellular processes (6). Additionally, cancer cells frequently express fetal isoforms of metabolic enzymes that are subject to different regulatory mechanisms to provide growth advantages (7). Gaining a systematic understanding of the metabolic changes that occur during carcinogenesis can thus be exploited for therapeutic and diagnostic purposes.Stable isotope-resolved metabolomics (SIRM) is a powerful approach developed by others and by us where isotopically enriched precursors such as [ 13 C 6 ]Glc are administered to a biological system, and the ensuing metabolic transformations are determined using appropriate analytic techniques to enable robust reconstruction of metabolic pathways (8 -11). Stable isotopes are non-radioactive and in SIRM practice are identical chemically and functionally to the most abundant isotope of that element. Incorporating stable isotopes such as 2 H, 13 C, or 15 N into biological precursors has long been used to trace their metabolism in living systems (12). SIRM is thus distinct from non-tracer-based metabolomics profiling for statistical models. Here, we review SIRM applications and demonstrate h...

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“…For example, SDHD KO mice were found embryonically lethal (35). SDHB KO mammalian cell lines failed to exert CII activity and featured a reduced proliferation rate (36,37). A seminal study linking mutations in FIGURE 2.…”

Section: B-d)mentioning

confidence: 99%

The Assembly Factor SDHAF2 Is Dispensable for Flavination of the Catalytic Subunit of Mitochondrial Complex II in Breast Cancer Cells

Bezawork-Geleta

Dong

Rohlena

et al. 2016

Journal of Biological Chemistry

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Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism

Cited by 190 publications

References 39 publications

Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer–Predisposing Mutations in Pheochromocytomas and Paragangliomas

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

The Assembly Factor SDHAF2 Is Dispensable for Flavination of the Catalytic Subunit of Mitochondrial Complex II in Breast Cancer Cells

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