The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
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DOI：
10.1038/nature06734
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发表时间：
2008-03-13
期刊：
影响因子：
64.8
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
--
作者：
Christofk, Heather R.;Vander Heiden, Matthew G.;Cantley, Lewis C.
许多肿瘤细胞具有升高的葡萄糖摄取速率，但降低的氧化磷酸化速率。这种肿瘤在氧气存在下持续产生高乳酸的现象，被称为有氧糖酵解，由Otto瓦尔堡在75年前首次注意到（1）。肿瘤细胞如何建立这种改变的代谢表型，以及它是否是肿瘤发生所必需的，目前还不清楚。在这里，我们表明，在糖酵解酶丙酮酸激酶的剪接异构体的一个单一的开关是必要的细胞代谢有氧糖酵解的转变，这促进肿瘤的发生。肿瘤细胞已显示仅表达丙酮酸激酶的胚胎M2亚型（2）。在这里，我们使用短发夹RNA敲低人癌细胞系中丙酮酸激酶M2的表达，并将其替换为丙酮酸激酶M1。将丙酮酸激酶表达转换为M1（成人）亚型导致瓦尔堡效应逆转，如通过乳酸产生减少和耗氧量增加所判断的，这与裸鼠异种移植物形成肿瘤的能力降低相关。这些结果表明，M2表达是有氧糖酵解所必需的，并且这种代谢表型为体内肿瘤细胞提供了选择性生长优势。
Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago(1). How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase(2). Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 ( adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.