Washington University in St. Louis

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Metabolomics to elucidate novel biochemical mechanisms of disease
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Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress

Gelman SJ, Naser FJ, Mahieu NG, McKenzie LD, Dunn GP, Cheeda MG, and Patti GJ
Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress
Cell Reports, 22, 512-522, 2018
doi:10.1016/j.celrep.2017.12.050

Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) occur in multiple types of human cancer. Here, we show that these mutations significantly disrupt NADPH homeostasis by consuming NADPH for 2-hydroxyglutarate (2-HG) synthesis. Cells respond to 2-HG synthesis, but not exogenous administration of 2-HG, by increasing pentose phosphate pathway (PPP) flux. We show that 2-HG production competes with reductive biosynthesis and the buffering of oxidative stress, processes that also require NADPH. IDH1 mutants have a decreased capacity to synthesize palmitate and an increased sensitivity to oxidative stress. Our results demonstrate that, even when NADPH is limiting, IDH1 mutants continue to synthesize 2-HG at the expense of other NADPH-requiring pathways that are essential for cell viability. Thus, rather than attempting to decrease 2-HG synthesis in the clinic, the consumption of NADPH by mutant IDH1 may be exploited as a metabolic weakness that sensitizes tumor cells to ionizing radiation, a commonly used anti-cancer therapy.

Washington University, Departments of Chemistry, Genetics, and Medicine. Saint Louis, Missouri 63110 USA