title: Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway.
abstract: Mammalian target of rapamycin (mTOR) signaling pathways have been shown to be activated in thyroid cancer. Recent evidences have demonstrated that the antidiabetic agent metformin, an activator of 5'-AMP-activated protein kinase, can impair the proliferation and migration of cancer cells via inhibition of mTOR. However, the underlying mechanisms remain unclear. In this study, we show that metformin can inhibit mTOR pathway to impair growth and migration of the thyroid cancer cell lines. Cyclin D1 and c-Myc are important regulators of cancer cell growth, and we observed that treatment of thyroid cancer cells with metformin reduced c-Myc and cyclin D1 expression through suppression of mTOR and subsequent inhibition of P70S6K1 and 4E-BP1 phosphorylation. Metformin reduced epithelial to mesenchymal transition (EMT) in thyroid carcinoma cells. Moreover, metformin regulated expression of the EMT-related markers E-cadherin, N-cadherin, and Snail. Additionally, knockdown of TSC2, the upstream regulatory molecule of mTOR pathway, or treatment of rapamycin, the mTOR inhibitor, could abolish the effects of metformin to regulate thyroid cancer cell proliferation, migration, EMT, and mTOR pathway molecules. These results indicate that metformin can suppress the proliferation, migration, and EMT of thyroid cancer cell lines by inhibiting mTOR signaling. These findings suggest that metformin and its molecular targets may be useful in thyroid carcinoma therapy.
authors: Department of Endocrinology and Metabolism, The 264 Hospital of PLA, 30 Qiao-Dong Street, Taiyuan, 030000, Shanxi, China.
authors: Baiyu
authors: B
authors: Han
authors: Hanzhi
authors: H
authors: Cui
authors: Lei
authors: L
authors: Kang
authors: Xuelin
authors: X
authors: Zhang
authors: Zhitao
authors: Z
authors: Jin
authors: Lanmin
authors: L
authors: Lu
authors: Zhongyi
authors: Z
authors: Fan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases