Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress.
Consumption of NADPH for 2-HG Synthesis Increases Pentose Phosphate Pathway Flux and Sensitizes Cells to Oxidative Stress.
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DOI：
10.1016/j.celrep.2017.12.050
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发表时间：
2018-01-09
期刊：
影响因子：
8.8
通讯作者：
Patti GJ
中科院分区：
文献类型：
--
作者：
Gelman SJ;Naser F;Mahieu NG;McKenzie LD;Dunn GP;Chheda MG;Patti GJ
异柠檬酸脱氢酶1（IDH 1）的功能获得性突变发生在多种人类癌症中。在这里，我们表明，这些突变显着破坏NADPH的稳态消耗NADPH的2-羟基戊二酸（2-HG）的合成。细胞通过增加戊糖磷酸途径（PPP）流量对2-HG合成做出反应，但对外源性2-HG给药没有反应。我们发现，2-HG生产竞争还原性生物合成和氧化应激的缓冲，也需要NADPH的过程。IDH 1突变体合成棕榈酸的能力降低，对氧化应激的敏感性增加。我们的研究结果表明，即使当NADPH是有限的，IDH 1突变体继续合成2-HG在其他NADPH需要的途径，是必不可少的细胞活力的代价。因此，不是试图在临床中减少2-HG合成，而是突变IDH 1消耗NADPH可被用作使肿瘤细胞对电离辐射（一种常用的抗癌疗法）敏感的代谢弱点。简而言之：使用液相色谱/质谱（LC/MS）和稳定同位素示踪，Gelman等人发现IDH 1突变细胞中2-HG的产生导致戊糖磷酸途径活性增加，从而产生NADPH。2-HG的产生与其他NADPH依赖性途径竞争，并使细胞对氧化还原应激敏感。
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. 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.
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