Abstract
BackgroundTargeting glutamine metabolism in cancer has become an increasingly vibrant area of research. Mutant IDH1 (IDH1mut) gliomas are considered good candidates for targeting this pathway because of the contribution of glutamine to their newly acquired function: synthesis of 2-hydroxyglutarate (2HG).MethodsWe have employed a combination of 13C tracers including glutamine and glucose for investigating the metabolism of patient-derived IDH1mut glioma cell lines through NMR and LC/MS. Additionally, genetic loss-of-function (in vitro and in vivo) approaches were performed to unravel the adaptability of these cell lines to the inhibition of glutaminase activity.ResultsWe report the adaptability of IDH1mut cells’ metabolism to the inhibition of glutamine/glutamate pathway. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG. However, this effect on metabolism was not extended to viability; rather, our patient-derived IDH1mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition.ConclusionsMajor metabolic adaptations involved pathways that can generate glutamate by using alternative substrates from glutamine, such as alanine or aspartate. Indeed, asparagine synthetase was upregulated both in vivo and in vitro revealing a new potential therapeutic target for a combinatory approach with CB839 against IDH1mut gliomas.
Highlights
Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research
Glucose and Gln are the major carbon sources for tumor cells; glucose is known to be an essential nutrient for tumor survival and progression, recent investigations have highlighted the importance of Gln as a major nutrient employed by cancer cells [15,16,17] participating in different pathways such as (1) synthesis of fatty acids via reductive carboxylation under hypoxia, (2) replenishment of the Tricarboxylic acids (TCA) cycle under conditions of citrate usage as a biosynthetic precursor, providing the majority of oxaloacetate and aspartate, (3) glutathione (GSH) biosynthesis and nitrogen source for nucleotide biosynthesis, a process involved in cell division
Glutamine is a precursor of 2HG in vitro First, we evaluated the correlation between the global metabolism of patient-derived IDH1mut cell lines and 2HG production by treating our cell lines with AGI5198 (Fig. 1a), a specific inhibitor of the IDH1mut protein
Summary
Targeting glutamine metabolism in cancer has become an increasingly vibrant area of research. The glutaminase inhibitor CB839 generated a decrease in the production of the downstream metabolites of glutamate, including those involved in the TCA cycle and 2HG This effect on metabolism was not extended to viability; rather, our patient-derived IDH1mut cell lines display a metabolic plasticity that allows them to overcome glutaminase inhibition. Since Gln can serve as a carbon source to produce 2HG in IDH1mut cancers, GLS inhibitors may provide therapeutic benefit in the treatment of these gliomas. Little is known about the contribution of the Gln/Glu pathway to 2HG formation and the metabolic consequences of targeting GLS in IDH1mut gliomas. We have assessed the role of the Gln/Glu pathway on 2HG formation and cell growth in a panel of endogenously IDH1-mutated cell lines. Our in vivo models reveal this metabolic compensation of IDH1mut glioma against GLS inhibition and provide additional insights on potential combinatorial treatments
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