SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer
SIK2 promotes reprogramming of glucose metabolism through PI3K/AKT/HIF-1α pathway and Drp1-mediated mitochondrial fission in ovarian cancer
复制标题
SIK2 通过 PI3K/AKT/HIF-1 α 通路和 Drp1 介导的卵巢癌线粒体裂变促进葡萄糖代谢重编程
DOI：
10.1016/j.canlet.2019.10.029
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Liu, Shujuan
中科院分区：
文献类型：
--
作者：
Gao, Tian;Zhang, Xiaohong;Liu, Shujuan
盐诱导蛋白激酶2(SIK2)属于AMP活化蛋白激酶家族，参与调节包括脂肪酸氧化在内的多种生物学功能。然而，SIK2在卵巢癌(OC)细胞糖代谢重编程中的作用尚不清楚。在这里，我们发现SIK2主要通过两种机制显著增强OC细胞的Warburg效应。一方面，SIK2通过激活PI3K/AKT信号通路上调HIF-1α的表达，直接上调主要糖酵解基因的转录，促进糖酵解。另一方面，SIK2通过Ser616位点Drp1的磷酸化促进线粒体的分裂，抑制线粒体的氧化磷酸化。此外，SIK2还通过促进细胞增殖、抑制细胞凋亡以及促进上皮细胞向间充质细胞转化来促进OC细胞的生长和转移。此外，SIK2介导的糖代谢重编程在OC细胞的生长和转移中起着关键作用。综上所述，我们的研究结果表明，SIK2通过激活PI3K/AKT/HIF-1α通路和DRP1磷酸化介导的线粒体分裂来调节OC细胞的葡萄糖代谢，而DRP1磷酸化介导的线粒体分裂在OC细胞中起着关键的致癌作用。
Salt-inducible kinase 2 (SIK2), which belongs to the AMP-activated protein kinase family, modulates various biological functions including fatty acid oxidation. However, the role of SIK2 in glucose metabolism reprogramming remains unclear in ovarian cancer (OC) cells. Here, we found that SIK2 significantly enhanced the Warburg effect of OC cells mainly through two mechanisms. On the one hand, SIK2 upregulated the expression of HIF-1 alpha by activating the PI3K/AKT signaling pathway, which directly upregulated the transcription of major glycolytic genes to promote glycolysis. On the other hand, SIK2 promoted mitochondrial fission through phosphorylation of Drp1 at Ser616 site, which inhibited the mitochondrial oxidative phosphorylation. In addition, SIK2 promoted growth and metastasis of OC cells by promoting cell proliferation and inhibiting cell apoptosis, as well as enhancing the epithelial-mesenchymal transition. Moreover, the SIK2-mediated reprogramming of glucose metabolism played a critical role in growth and metastasis of OC cells. Collectively, our findings demonstrate that SIK2 is a crucial regulator of glucose metabolism in OC cells through activation of PI3K/AKT/HIF-1 alpha pathway and Drpl phosphorylation-mediated mitochondrial fission, which plays a critical oncogenic role in OC cells.