Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Sells.
Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Sells.
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DOI：
10.1016/j.celrep.2018.09.074
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发表时间：
2018-10-23
期刊：
影响因子：
8.8
通讯作者：
Metallo CM
中科院分区：
文献类型：
--
作者：
Badur MG;Muthusamy T;Parker SJ;Ma S;McBrayer SK;Cordes T;Magana JH;Guan KL;Metallo CM
NADP依赖的异柠檬酸脱氢酶(IDH1和IDH2)的新形态突变在几种癌症的发生中起作用。虽然重要的研究集中在与(D)2-羟基戊二酸(D2HG)积累相关的高甲基化表型上，但这些突变的代谢后果也可能提供治疗机会。在这里，我们将基于通量的方法应用于具有内源性IDH1突变的基因工程细胞系，以检验作为IDH1突变或表达的函数的D2HG产量增加和IDH通量改变对代谢的影响。IDH1突变细胞中D2HG的合成消耗NADPH的速度类似于从头脂肪生成。IDH1突变细胞的体外生长对外源脂源的依赖性增加，因为与表达野生型或酶失活等位基因的细胞相比，去除中间脂类会显著减缓IDH1突变细胞的生长。NADPH的再生可能限制了IDH1突变细胞的脂肪生成和潜在的氧化还原动态平衡，突出了细胞生物合成和氧化还原代谢之间的关键联系。Badur等人。应用代谢流量分析来了解IDH1的致癌突变如何改变氧化还原代谢。(D)2-羟基戊二酸(D2HG)的产生消耗NADPH的水平类似于从头开始脂肪生成，去掉脂质会影响IDH1突变细胞的体外生长。
Neomorphic mutations in NADP-dependent isocitrate dehydrogenases (IDH1 and IDH2) contribute to tumorigenesis in several cancers. Although significant research has focused on the hypermethylation phenotypes associated with (D)2-hydroxyglutarate (D2HG) accumulation, the metabolic consequences of these mutations may also provide therapeutic opportunities. Here we apply flux-based approaches to genetically engineered cell lines with an endogenous IDH1 mutation to examine the metabolic impacts of increased D2HG production and altered IDH flux as a function of IDH1 mutation or expression. D2HG synthesis in IDH1-mutant cells consumes NADPH at rates similar to de novo lipogenesis. IDH1-mutant cells exhibit increased dependence on exogenous lipid sources for in vitro growth, as removal of medium lipids slows growth more dramatically in IDH1-mutant cells compared with those expressing wild-type or enzymatically inactive alleles. NADPH regeneration may be limiting for lipogenesis and potentially redox homeostasis in IDH1-mutant cells, highlighting critical links between cellular biosynthesis and redox metabolism. Badur et al. apply metabolic flux analysis to understand how oncogenic mutations in IDH1 alter redox metabolism. Production of (D)2-hydroxyglutarate (D2HG) consumes NADPH at levels similar to de novo lipogenesis, and removal of lipids compromises in vitro growth of IDH1-mutant cells.
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影响因子：
11.1
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通讯作者：
Mallette, Frederick A.
影响因子：
50.3
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