IDH1 Mutation Induces Reprogramming of Pyruvate Metabolism

Abstract

Mutant isocitrate dehydrogenase 1 (IDH1) catalyzes the production of 2-hydroxyglutarate but also elicits additional metabolic changes. Levels of both glutamate and pyruvate dehydrogenase (PDH) activity have been shown to be affected in U87 glioblastoma cells or normal human astrocyte (NHA) cells expressing mutant IDH1, as compared to cells expressing wild-type IDH1. In this study, we show how these phenomena are linked through the effects of IDH1 mutation, which also reprograms pyruvate metabolism. Reduced PDH activity in U87 glioblastoma and NHA IDH1 mutant cells was associated with relative increases in PDH inhibitory phosphorylation, expression of pyruvate dehydrogenase kinase-3 and levels of hypoxia inducible factor-1α. PDH activity was monitored in these cells by hyperpolarized 13C-magnetic resonance spectroscopy (13C-MRS), which revealed a reduction in metabolism of hyperpolarized 2-13C-pyruvate to 5-13C-glutamate, relative to cells expressing wild-type IDH1. 13C-MRS also revealed a reduction in glucose flux to glutamate in IDH1 mutant cells. Notably, pharmacological activation of PDH by cell exposure to dichloroacetate (DCA) increased production of hyperpolarized 5-13C-glutamate in IDH1 mutant cells. Further, DCA treatment also abrogated the clonogenic advantage conferred by IDH1 mutation. Using patient-derived mutant IDH1 neurosphere models, we showed that PDH activity was essential for cell proliferation. Taken together, our results established that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism which is essential for cell proliferation and clonogenicity, with immediate therapeutic implications.

Metabolic reprogramming of pyruvate dehydrogenase is essential for the proliferation of glioma cells expressing mutant IDH1

“…In a recently published study (6), we confirmed that a significant reduction in PDH activity occurs in both our U87 and NHA mutant IDH1 cells compared to wild-type (6). 13 C MRS probing the fate of 1- 13 C-glucose to 4- 13 C-glutamate, and hyperpolarized 13 C MRS probing the fate of 2- 13 C-pyruvate to 5- 13 C-glutamate, showed that reduced PDH activity also resulted in a reduction in glucose flux to glutamate in IDH1 mutant cells relative to wild-type.…”

“…In summary, our recent study (6) identifies a potential therapeutic target for mutant IDH1 low-grade gliomas, as well as an associated companion MRS biomarker for agents that would modulate that target.…”

“…In a separate study we discovered that pyruvate dehydrogenase (PDH) activity was reduced in NHA IDH1 mutant cells (5). Given that PDH is an important regulatory point for glucose oxidation via the tricarboxylic acid (TCA) cycle and, as a result, for glutamate production, we questioned the role of PDH in IDH1 mutant glioma cells (6). …”

The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1-Mutant Cancers and Potentiates NAD+ Depletion–Mediated Cytotoxicity

“…As a common feature, however, mutant IDH1 drives widespread metabolic alterations in cancer cells(17). These include the production of 2-hydroxyglutarate (2HG)(18), modulation of HIF1α(19), pyruvate dehydrogenase(20), and lactate dehydrogenase(21), as well as altered citric acid cycle flux(22), and depleted steady-state pools of several canonical metabolites including glutathione(23) and nicotinamide adenine dinucleotide (NAD+)(24). This altered baseline metabolism results in the exposure of distinct enzymatic targets, including glutaminase(25) and the NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT)(24), to selective inhibition with small molecules, resulting in genotype-specific metabolic vulnerabilities in IDH mutant cancer cells.…”

Perfused Cells, Tissues and Organs by Magnetic Resonance Spectroscopy

“…26,27 Of recent interest is the use of labeled glucose to study the role of mutant isocitrate dehydrogenase on aggressive cancer phenotypes. 28 Since muscle tissue relies heavily on -oxidation for energy, labeled short, medium, and long chain fatty acids have been used to study metabolism under a range of conditions that include normal, ischemic, and diabetic perfused hearts. 29,30 The focus in liver perfusion has been somewhat different.…”