eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis
eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis
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eEF-2 激酶是通过控制 PP2A-A 合成来调节 Warburg 效应的关键因子
DOI：
10.1038/onc.2016.166
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发表时间：
2016-12-08
期刊：
影响因子：
8
通讯作者：
Yang, J-M
中科院分区：
文献类型：
--
作者：
Cheng, Y.;Ren, X.;Yang, J-M
癌细胞主要通过糖酵解代谢葡萄糖来产生能量，以满足其代谢需求，这种现象被称为Warburg效应。尽管Warburg效应被认为是一种对癌细胞存活和增殖至关重要的特性，但这种现象背后的调节机制仍不完全清楚。我们在这里报道真核延伸因子-2激酶（eEF-2K），蛋白质合成的负调节因子，在促进癌细胞糖酵解中起关键作用。我们发现，在肿瘤细胞和ras转化的小鼠胚胎成纤维细胞中，eEF-2K的缺乏显著降低了葡萄糖的摄取，并减少了乳酸和三磷酸腺苷的产生。我们进一步证明eEF-2K对糖酵解的促进作用是由于激酶介导的蛋白磷酸酶2A-A （PP2A-A）的合成限制，PP2A-A是促进c-Myc蛋白泛素蛋白酶体降解的关键因子，因为eEF-2K表达下调导致PP2A-A蛋白合成显著增加，c-Myc和丙酮酸激酶M2异构体显著下调，c-Myc转录激活的关键糖酵解酶。此外，eEF-2K的缺失降低了转化细胞的增殖能力，增强了肿瘤细胞对化疗的敏感性，无论在体内还是体外。这些结果揭示了eef - 2k介导的PP2A-A在肿瘤细胞糖酵解中的作用，为Warburg效应的调控提供了新的见解。
Cancer cells predominantly metabolize glucose by glycolysis to produce energy in order to meet their metabolic requirement, a phenomenon known as Warburg effect. Although Warburg effect is considered a peculiarity critical for survival and proliferation of cancer cells, the regulatory mechanisms behind this phenomenon remain incompletely understood. We report here that eukaryotic elongation factor-2 kinase (eEF-2K), a negative regulator of protein synthesis, has a critical role in promoting glycolysis in cancer cells. We showed that deficiency in eEF-2K significantly reduced the uptake of glucose and decreased the productions of lactate and adenosine triphosphate in tumor cells and in the Ras-transformed mouse embryonic fibroblasts. We further demonstrated that the promotive effect of eEF-2K on glycolysis resulted from the kinase-mediated restriction of synthesis of the protein phosphatase 2A-A (PP2A-A), a key factor that facilitates the ubiquitin-proteasomal degradation of c-Myc protein, as knockdown of eEF-2K expression led to a significant increase in PP2A-A protein synthesis and remarkable downregulation of c-Myc and pyruvate kinase M2 isoform, the key glycolytic enzyme transcriptionally activated by c-Myc. In addition, depletion of eEF-2K reduced the ability of the transformed cells to proliferate and enhanced the sensitivity of tumor cells to chemotherapy both in vitro and in vivo. These results, which uncover a role of the eEF-2K-mediated control of PP2A-A in tumor cell glycolysis, provide new insights into the regulation of the Warburg effect.