PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation.
PARP14 promotes the Warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation.
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DOI：
10.1038/ncomms8882
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发表时间：
2015-08-10
影响因子：
16.6
通讯作者：
Papa S
中科院分区：
文献类型：
--
作者：
Iansante V;Choy PM;Fung SW;Liu Y;Chai JG;Dyson J;Del Rio A;D'Santos C;Williams R;Chokshi S;Anders RA;Bubici C;Papa S
大多数肿瘤细胞利用有氧糖酵解(Warburg效应)来支持合成代谢生长和逃避细胞凋亡。有趣的是，将Warburg效应与抑制细胞凋亡联系起来的分子机制还不是很清楚。在这项研究中，利用体外和体内的功能丧失研究，我们证明了抗凋亡蛋白聚(ADP-核糖)聚合酶(PARP)14通过维持丙酮酸激酶M2亚型(PKM2)的低活性来促进人肝细胞癌(HCC)的有氧糖酵解，PKM2是Warburg效应的关键调节因子。值得注意的是，PARP14在肝细胞癌原发肿瘤中高表达，与患者预后不良有关。在机制上，PARP14抑制促凋亡蛋白激酶JNK1，而JNK1通过Thr365的磷酸化而激活PKM2。此外，靶向PARP14增强了肝癌细胞对抗肝癌药物的敏感性。我们的发现表明，PARP14-JNK1-PKM2调节轴是肿瘤细胞Warburg效应的重要决定因素，并在细胞凋亡和新陈代谢之间提供了一种机制联系。肿瘤细胞可以通过避开细胞死亡途径并改变其新陈代谢来适应局部环境而存活。在这项研究中，Iansante等人。结果表明，抗凋亡蛋白PARP14保持较低的PKM2活性，导致糖酵解增强，表明抑制细胞凋亡与代谢改变之间存在联系。
Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo, we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism. Tumour cells can survive by evading cell death pathways and altering their metabolism to adapt to their local environment. In this study, Iansante et al. show that the anti-apoptotic protein PARP14 maintains low PKM2 activity, leading to enhanced glycolysis, demonstrating a link between suppression of apoptosis and altered metabolism.