Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth
Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth
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DOI：
10.1073/pnas.1014769108
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发表时间：
2011-03-08
影响因子：
11.1
通讯作者：
Zhang, Hongbing
中科院分区：
文献类型：
--
作者：
Sun, Qian;Chen, Xinxin;Zhang, Hongbing
尽管有氧糖酵解（瓦尔堡效应）是癌症的标志，但关键问题，包括癌细胞何时、如何以及为什么变得高度糖酵解，仍然不太清楚。对于一个很大程度上未知的调节机制，限速糖酵解酶丙酮酸激酶M2（PKM 2）亚型仅在胚胎，增殖和肿瘤细胞中表达，并在肿瘤代谢和生长中发挥重要作用。由于受体酪氨酸激酶/PI 3 K/AKT/哺乳动物雷帕霉素靶蛋白（RTK/PI 3 K/AKT/mTOR）信号级联是癌症中经常改变的通路，我们探讨了其在癌症代谢中的潜在作用。我们通过在常氧条件下诱导PKM 2和其他糖酵解酶，将mTOR鉴定为瓦尔堡效应的中枢激活剂。由于结节性硬化症复合物2的缺乏和随后的mTOR激活，PKM 2水平在小鼠肾肿瘤中增加，并且通过mTOR抑制在人癌细胞中降低。PKM 2表达的mTOR上调是通过低氧诱导因子1 α（HIF 1 α）介导的转录激活和PKM 2基因剪接的c-Myc-异质核核糖核蛋白（hnRNP）依赖性调节。PKM 2的破坏抑制致癌mTOR介导的肿瘤发生。与正常细胞不同，mTOR过度活跃的细胞对mTOR或糖酵解的抑制更敏感。mTOR和糖酵解的双重抑制协同地减弱了mTOR高活性细胞的增殖和肿瘤发展。尽管有氧糖酵解对于永生化和转化的衰老破坏不是必需的，但在多步致癌过程中频繁失调的mTOR信号传导可能有助于许多癌症中瓦尔堡效应的发展。mTOR/HIF 1 α/Myc-hnRNP/PKM 2糖酵解信号网络的组分可以被靶向用于治疗由异常RTK/PI 3 K/AKT/mTOR信号通路引起的癌症。
Although aerobic glycolysis (the Warburg effect) is a hallmark of cancer, key questions, including when, how, and why cancer cells become highly glycolytic, remain less clear. For a largely unknown regulatory mechanism, a rate-limiting glycolytic enzyme pyruvate kinase M2 (PKM2) isoform is exclusively expressed in embryonic, proliferating, and tumor cells, and plays an essential role in tumor metabolism and growth. Because the receptor tyrosine kinase/PI3K/AKT/mammalian target of rapamycin (RTK/PI3K/AKT/mTOR) signaling cascade is a frequently altered pathway in cancer, we explored its potential role in cancer metabolism. We identified mTOR as a central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes under normoxic conditions. PKM2 level was augmented in mouse kidney tumors due to deficiency of tuberous sclerosis complex 2 and consequent mTOR activation, and was reduced in human cancer cells by mTOR suppression. mTOR up-regulation of PKM2 expression was through hypoxia-inducible factor 1 alpha (HIF1 alpha)-mediated transcription activation, and c-Myc-heterogeneous nuclear ribonucleoproteins (hnRNPs)-dependent regulation of PKM2 gene splicing. Disruption of PKM2 suppressed oncogenic mTOR-mediated tumorigenesis. Unlike normal cells, mTOR hyperactive cells were more sensitive to inhibition of mTOR or glycolysis. Dual suppression of mTOR and glycolysis synergistically blunted the proliferation and tumor development of mTOR hyperactive cells. Even though aerobic glycolysis is not required for breach of senescence for immortalization and transformation, the frequently deregulated mTOR signaling during multistep oncogenic processes could contribute to the development of the Warburg effect in many cancers. Components of the mTOR/HIF1 alpha/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway.