ARHGAP4 mediates the Warburg effect in pancreatic cancer through the mTOR and HIF-1α signaling pathways
ARHGAP4 mediates the Warburg effect in pancreatic cancer through the mTOR and HIF-1α signaling pathways
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ARHGAP4 通过 mTOR 和 HIF-1 α 信号通路介导胰腺癌中的 Warburg 效应
DOI：
10.2147/ott.s207560
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发表时间：
2019-01-01
影响因子：
4
通讯作者：
Liu, Luming
中科院分区：
文献类型：
--
作者：
Shen, Yehua;Chen, Gang;Liu, Luming
目的：在有氧条件下，癌细胞剧烈地表现出糖酵解与乳酸分泌和线粒体活性降低的现象，历史上被称为Warburg效应。Rho gtpase - activation protein 4 （ARHGAP4）是与肿瘤发生相关的Rho信号通路的重要负调控因子。我们的研究旨在确定ARHGAP4在体外控制胰腺癌糖酵解过程中的功能及其可能的分子机制。方法：采用免疫组化方法检测胰腺癌组织中ARHGAP4和PKM2的表达。用mTOR抑制剂（雷帕霉素）或HIF-1 α抑制剂（YC-1）处理转染了慢病毒或siRNA的人胰腺癌细胞，分析其对细胞活力、葡萄糖摄取、乳酸释放以及ARHGAP4、p-mTOR、mTOR、PKM2和HIF-1 α表达水平的影响。结果：我们的研究结果显示，胰腺癌组织中ARHGAP4和PKM2的表达分别下调和上调。ARHGAP4过表达显著抑制胰腺癌细胞活力、葡萄糖摄取、乳酸释放、PKM2表达以及mTOR和HIF-1 α信号通路的激活，而ARHGAP4沉默和雷帕霉素或YC-1的处理则表现出相反的作用。此外，ARHGAP4下调诱导的胰腺癌细胞形态被雷帕霉素或YC-1治疗抑制。结论：mTOR和HIF-1 α信号通路可调控arhgap4介导的胰腺癌糖酵解过程。
Objective: The phenomenon that cancer cells avidly exhibit glycolysis with lactate secretion and decrease in mitochondrial activity under aerobic conditions is known historically as the Warburg effect. Rho GTPase-activating protein 4 (ARHGAP4) is an important negative regulator of the Rho signaling pathway that was associated with the tumorigenesis. Our study aims to determine the function of ARHGAP4 in controlling the glycolytic process of pancreatic cancer in vitro and possible molecular mechanism involved.Methods: ARHGAP4 and PKM2 expressions in pancreatic cancer tissues were measured by immunohistochemistry. Human pancreatic cancer cells transfected with ARHGAP4 expressing lentivirus or siRNA were treated with either mTOR inhibitor (Rapamycin) or HIF-1 alpha inhibitor (YC-1), and the effects were analyzed on cell viability, glucose uptake, lactate release, and the levels of ARHGAP4, p-mTOR, mTOR, PKM2, and HIF-1 alpha expression.Results: Our findings showed that ARHGAP4 and PKM2 expressions were, respectively, down-regulated and up-regulated in pancreatic cancer tissues. Overexpression of ARHGAP4 significantly inhibited cell viability, glucose uptake, lactate release, PKM2 expression, and activation of mTOR and HIF-1 alpha signaling pathways in pancreatic cancer cells while ARHGAP4 silencing and treatment of Rapamycin or YC-1 showed inverse effects. Additionally, ARHGAP4 downregulation induced cell morphology of pancreatic cancer was inhibited by Rapamycin or YC-1 treatment.Conclusion: These findings suggest that mTOR and HIF-1 alpha signaling pathways can regulate the ARHGAP4-mediated glycolytic process of pancreatic cancer.