Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress
| Autor: | Gavin P. Dunn, Fuad J. Naser, Milan G. Chheda, Susan J. Gelman, Gary J. Patti, Nathaniel G. Mahieu, Lisa D. McKenzie |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Chemistry Mutant Pentose phosphate pathway medicine.disease_cause General Biochemistry Genetics and Molecular Biology Article 3. Good health Cell biology Pentose Phosphate Pathway 03 medical and health sciences chemistry.chemical_compound Oxidative Stress 030104 developmental biology Isocitrate dehydrogenase Biosynthesis lcsh:Biology (General) medicine Humans Viability assay Flux (metabolism) lcsh:QH301-705.5 Homeostasis Oxidative stress NADP |
| Zdroj: | Cell Reports, Vol 22, Iss 2, Pp 512-522 (2018) Cell reports |
| ISSN: | 2211-1247 |
| Popis: | Summary Gain-of-function mutations in isocitrate dehydroge-nase 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. Graphical Abstract In Brief: 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. |
| Databáze: | OpenAIRE |
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