Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway
Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway
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DOI：
10.1007/s13277-015-3315-4
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发表时间：
2015-08-01
期刊：
影响因子：
--
通讯作者：
Fan, Zhongyi
中科院分区：
文献类型：
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作者：
Han, Baiyu;Cui, Hanzhi;Fan, Zhongyi
哺乳动物雷帕霉素靶（mTOR）信号通路已被证明在甲状腺癌中被激活。最近的证据表明，降糖药二甲双胍是一种5'- amp活化蛋白激酶的激活剂，可以通过抑制mTOR来损害癌细胞的增殖和迁移。然而，潜在的机制仍不清楚。在这项研究中，我们发现二甲双胍可以抑制mTOR通路，从而损害甲状腺癌细胞系的生长和迁移。Cyclin D1和c-Myc是癌细胞生长的重要调节因子，我们观察到二甲双胍治疗甲状腺癌细胞通过抑制mTOR和随后抑制P70S6K1和4E-BP1磷酸化来降低c-Myc和Cyclin D1的表达。二甲双胍减少甲状腺癌细胞上皮向间质转化（EMT）。此外，二甲双胍调节emt相关标志物E-cadherin、N-cadherin和Snail的表达。此外，敲低mTOR通路上游调控分子TSC2，或治疗mTOR抑制剂雷帕霉素，可消除二甲双胍调节甲状腺癌细胞增殖、迁移、EMT和mTOR通路分子的作用。这些结果表明，二甲双胍可以通过抑制mTOR信号传导抑制甲状腺癌细胞的增殖、迁移和EMT。这些发现提示二甲双胍及其分子靶点可能在甲状腺癌治疗中有用。
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.