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Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway

  • Research Article
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Tumor Biology

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.

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Acknowledgments

The authors wish to thank Dr. JT Dou for his help and support.

Conflicts of interest

None

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    Authors and Affiliations

    1. Department of Endocrinology and Metabolism, The 264 Hospital of PLA, 30 Qiao-Dong Street, Taiyuan, 030000, Shanxi, China

      Baiyu Han, Lanmin Lu & Zhongyi Fan

    2. Department of Oncology, PLA General Hospital, Beijing, China

      Baiyu Han & Zhongyi Fan

    3. Department of Oncology, 309th Hostital of PLA, Beijing, China

      Hanzhi Cui

    4. Department of Nuclear Medicine, Peking University First Hospital, Beijing, China

      Lei Kang

    5. Department of Respiration, PLA General Hospital, Beijing, China

      Xuelin Zhang

    6. Department of Cardiology, General Hospital of the Second Artillery, Beijing, China

      Zhitao Jin

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    1. Baiyu Han
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    4. Xuelin Zhang
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    Correspondence to Lanmin Lu or Zhongyi Fan.

    Additional information

    Baiyu Han, Hanzhi Cui, and Lei Kang contributed equally to this work. The 264 Hospital of PLA Chinese and PLA General Hospital also contributed equally to this work

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    Han, B., Cui, H., Kang, L. et al. Metformin inhibits thyroid cancer cell growth, migration, and EMT through the mTOR pathway. Tumor Biol. 36, 6295–6304 (2015). https://doi.org/10.1007/s13277-015-3315-4

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    • DOI: https://doi.org/10.1007/s13277-015-3315-4

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