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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

Ke-yan Cheng, Min Hao

(Department of Obstetrics and Gynecology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China (mainland))

Med Sci Monit 2017; 23:2017-2028

DOI: 10.12659/MSM.901542

Published: 2017-04-27


BACKGROUND: 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.
MATERIAL AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

Keywords: Uterine Cervical Neoplasms, Substance Abuse Treatment Centers, Biosynthetic Pathways



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