Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells.
Addiction to Coupling of the Warburg Effect with Glutamine Catabolism in Cancer Cells.
复制标题
癌细胞中沃尔堡效应与谷氨酰胺分解代谢的偶联成瘾。
DOI：
10.1016/j.celrep.2016.09.045
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发表时间：
2016-10-11
期刊：
影响因子：
8.8
通讯作者：
Munger J
中科院分区：
文献类型：
--
作者：
Smith B;Schafer XL;Ambeskovic A;Spencer CM;Land H;Munger J
代谢重编程对肿瘤发生至关重要，但这种深刻重组的出现和功能仍然知之甚少。在这里，我们发现协同致癌突变驱动大规模代谢重编程，这既是癌细胞固有的，也是向恶性转化的必要条件。这涉及编码代谢酶的几个基因的协同调节，包括乳酸脱氢酶LDHA和LDHB以及线粒体谷氨酸丙酮酸转氨酶2（GPT2）。值得注意的是，GPT2参与活化的糖酵解以驱动谷氨酰胺作为结肠癌细胞中TCA循环回补的碳源的利用。我们的数据表明，瓦尔堡效应支持肿瘤的发生，通过GPT2介导的耦合丙酮酸生产谷氨酰胺催化剂。虽然对癌症表型至关重要，但GPT2活性在未完全转化的细胞中被抑制，从而精确定位与癌细胞进展为恶性肿瘤特异性相关的代谢脆弱性。
Metabolic reprogramming is critical to oncogenesis, but the emergence and function of this profound reorganization remain poorly understood. Here we find that cooperating oncogenic mutations drive large-scale metabolic reprogramming, which is both intrinsic to cancer cells and obligatory for the transition to malignancy. This involves synergistic regulation of several genes encoding metabolic enzymes, including the lactate dehydrogenases LDHA and LDHB and mitochondrial glutamic pyruvate transaminase 2 (GPT2). Notably, GPT2 engages activated glycolysis to drive the utilization of glutamine as a carbon source for TCA cycle anaplerosis in colon cancer cells. Our data indicate that the Warburg effect supports oncogenesis via GPT2-mediated coupling of pyruvate production to glutamine catabolism. Although critical to the cancer phenotype, GPT2 activity is dispensable in cells that are not fully transformed, thus pinpointing a metabolic vulnerability specifically associated with cancer cell progression to malignancy.