Mammalian Target of Rapamycin (mTOR) Regulates Transforming Growth Factor-β1 (TGF-β1)-Induced Epithelial-Mesenchymal Transition via Decreased Pyruvate Kinase M2 (PKM2) Expression in Cervical Cancer Cells.
Mammalian Target of Rapamycin (mTOR) Regulates Transforming Growth Factor-β1 (TGF-β1)-Induced Epithelial-Mesenchymal Transition via Decreased Pyruvate Kinase M2 (PKM2) Expression in Cervical Cancer Cells.
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DOI：
10.12659/msm.901542
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发表时间：
2017-04-27
期刊：
影响因子：
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通讯作者：
Hao M
中科院分区：
文献类型：
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作者：
Cheng KY;Hao M
上皮间质转化（EMT）在癌症发生中发挥着重要作用。转化生长因子β1（TGF-β1）可以诱导EMT，从而增加肿瘤的迁移和侵袭。此外，最近的研究已证明哺乳动物雷帕霉素靶点（mTOR）是EMT的关键调节因子。我们研究了 mTOR 在转化生长因子 β1 (TGF-β1) 诱导的宫颈癌细胞 EMT 中的机制。用 10 ng/ml TGF-β1 处理 HeLa 和 SiHa 细胞以诱导 EMT。然后，他们接受或不接受雷帕霉素治疗。进行CCK8测定以确定细胞增殖。通过伤口愈合实验检测细胞迁移；通过流式细胞术分析细胞凋亡； mTOR 抑制剂抑制 mTOR 通路以评估 E-cadherin、Vimentin STAT3、Snail2、p-p70s6k 和 PKM2 表达的表达。 TGF-β1 促进宫颈癌细胞的增殖和迁移，并减弱细胞凋亡。 Rapamycin 消除 TGF-β1 诱导的 EMT 细胞增殖和迁移，并逆转 TGF-β1 诱导的 EMT。在用 TGF-β1 刺激后，HeLa 和 SiHa 细胞中的 E-钙粘蛋白受到抑制，而波形蛋白和 PKM2 则增加。此外，mTOR在TGF-β1诱导的EMT过程中被激活。雷帕霉素抑制 p70s6k 的磷酸化。此外，抑制 mTOR 通路会降低 PKM2 的表达。抑制 mTOR 通路可消除 TGF-β1 诱导的 EMT 并减少 mTOR/p70s6k 信号传导，从而下调 PKM2 表达。我们的结果为抑制 mTOR 的抗肿瘤作用提供了新的机制见解。
Epithelial-mesenchymal transition (EMT) plays an important role in cancer tumorigenesis. Transforming growth factor β1 (TGF-β1) can induced EMT, which could increase tumor migration and invasion. Moreover, recent studies have been proven that mammalian target of rapamycin (mTOR) is a critical regulator of EMT. We investigated the mechanisms of mTOR in transforming growth factor β1 (TGF-β1)-induced EMT in cervical cancer cells. HeLa and SiHa cells were treated with 10 ng/ml TGF-β1 to induce EMT. Then, they were treated with or without rapamycin. CCK8 assay was performed to determine cell proliferation. Cell migration was detected by wound-healing assay; apoptosis was analyzed by flow cytometry; mTOR inhibitors inhibited mTOR pathway to assess the expression of E-cadherin, Vimentin STAT3, Snail2, p-p70s6k, and PKM2 expression. TGF-β1 promoted proliferation and migration, and attenuated apoptosis in cervical carcinoma cells. Rapamycin abolished TGF-β1-induced EMT cell proliferation and migration and reversed TGF-β1-induced EMT. E-cadherin were suppressed, whereas Vimentin and PKM2 were increased in HeLa and SiHa cells after stimulation with TGF-β1. Moreover, mTOR was activated in the process of TGF-β1-induced EMT. Rapamycin inhibited the phosphorylation of p70s6k. Furthermore, inhibition of the mTOR pathway decreased PKM2 expression. Inhibition of the mTOR pathway abolished TGF-β1-induced EMT and reduced mTOR/p70s6k signaling, which downregulated PKM2 expression. Our results provide novel mechanistic insight into the anti-tumor effects of inhibition of mTOR.