Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress

Susan J. Gelman, Fuad Naser, Nathaniel G. Mahieu, Lisa D. McKenzie, Gavin P. Dunn, Milan G. Chheda, Gary J. Patti

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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. Using liquid chromatography/mass spectrometry (LC/MS) and stable isotope tracing, Gelman et al. find that 2-HG production in cells with IDH1 mutations leads to increased pentose phosphate pathway activity to generate NADPH. Production of 2-HG competes with other NADPH-dependent pathways and sensitizes cells to redox stress.

Original languageEnglish
Pages (from-to)512-522
Number of pages11
JournalCell Reports
Volume22
Issue number2
DOIs
StatePublished - 2018

Keywords

  • 2-hydroxyglutarate
  • LC/MS
  • cancer metabolism
  • metabolomcis
  • pentose phosphate pathway
  • redox regulation

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