Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth
Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth
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DOI：
10.1038/msb.2011.56
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发表时间：
2011-08-01
影响因子：
9.9
通讯作者：
Chiaradonna, Ferdinando
中科院分区：
文献类型：
--
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
癌基因如K-ras介导肿瘤发生过程中的细胞和代谢转化。为了分析k - ras依赖性代谢改变，我们采用了C-13代谢通量分析（MFA）、n- 15标记谷氨酰胺的非靶向示踪命运检测（NTFD）以及小鼠成纤维细胞和人类癌细胞系的转录组学分析。稳定同位素标记的葡萄糖和谷氨酰胺示踪剂和细胞内通量的计算测定表明，表达致癌K-Ras的细胞表现出增强的糖酵解活性，通过三羧酸（TCA）循环的氧化通量减少，并增加了谷氨酰胺在合成代谢中的利用。令人惊讶的是，在两种转化细胞系中都检测到TCA循环相关代谢物的非规范标记。转录谱检测到与糖酵解、谷氨酰胺代谢和核苷酸生物合成相关的几个基因在转化为致癌K-Ras后表达升高。沿着这些途径的酶的化学扰动进一步支持糖酵解和TCA代谢的解耦，谷氨酰胺提供增加的碳来驱动TCA循环。这些结果为致癌K-Ras在癌细胞代谢重编程中的作用提供了证据。生物工程学报（英文版）；2011年8月16日在线发布；doi: 10.1038 / msb.2011.56
Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed C-13 metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of N-15-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells. Molecular Systems Biology 7: 523; published online 16 August 2011; doi:10.1038/msb.2011.56