Tumor Biology

, Volume 36, Issue 8, pp 6295–6304 | Cite as

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

  • Baiyu Han
  • Hanzhi Cui
  • Lei Kang
  • Xuelin Zhang
  • Zhitao Jin
  • Lanmin LuEmail author
  • Zhongyi FanEmail author
Research Article


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.


Metformin Thyroid cancer mTOR Cell proliferation Cell migration EMT 



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

Conflicts of interest


Supplementary material

13277_2015_3315_MOESM1_ESM.pdf (34 kb)
Supplementary Fig. 1 (PDF 34 kb)
13277_2015_3315_MOESM2_ESM.pdf (802 kb)
Supplementary Fig. 2 (PDF 801 kb)
13277_2015_3315_MOESM3_ESM.pdf (487 kb)
Supplementary Fig. 3 (PDF 487 kb)


  1. 1.
    Chen AY, Jemal A, Ward EM. Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer. 2009;115:3801–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  3. 3.
    Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, Sjodin A, et al. International patterns and trends in thyroid cancer incidence, 1973–2002. Cancer Causes Control. 2009;20:525–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13:184–99.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Liu D, Xing J, Trink B, Xing M. BRAF mutation-selective inhibition of thyroid cancer cells by the novel MEK inhibitor RDEA119 and genetic-potentiated synergism with the mTOR inhibitor temsirolimus. Int J Cancer. 2010;127:2965–73.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest. 2005;115:94–101.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006;6:292–306.CrossRefPubMedGoogle Scholar
  8. 8.
    Liu Z, Hou P, Ji M, Guan H, Studeman K, Jensen K, et al. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab. 2008;93:3106–16.CrossRefPubMedGoogle Scholar
  9. 9.
    Crandall JP, Knowler WC, Kahn SE, Marrero D, Florez JC, Bray GA, et al. Diabetes prevention program research, the prevention of type 2 diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:382–93.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Witters LA. The blooming of the French lilac. J Clin Invest. 2001;108:1105–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kato K, Gong J, Iwama H, Kitanaka A, Tani J, Miyoshi H, et al. The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther. 2012;11:549–60.CrossRefPubMedGoogle Scholar
  13. 13.
    Lea MA, Pourat J, Patel R, des Bordes C. Growth inhibition of colon cancer cells by compounds affecting AMPK activity. World J Gastrointest Oncol. 2014;6:244–52.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2011;15:166–78.CrossRefPubMedGoogle Scholar
  15. 15.
    Chen G, Xu S, Renko K, Derwahl M. Metformin inhibits growth of thyroid carcinoma cells, suppresses self-renewal of derived cancer stem cells, and potentiates the effect of chemotherapeutic agents. J Clin Endocrinol Metab. 2012;97:E510–20.CrossRefPubMedGoogle Scholar
  16. 16.
    Cho SW, Yi KH, Han SK, Sun HJ, Kim YA, Oh BC, et al. Therapeutic potential of metformin in papillary thyroid cancer in vitro and in vivo. Mol Cell Endocrinol. 2014;393:24–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Klubo-Gwiezdzinska J, Jensen K, Costello J, Patel A, Hoperia V, Bauer A, et al. Metformin inhibits growth and decreases resistance to anoikis in medullary thyroid cancer cells. Endocr Relat Cancer. 2012;19:447–56.CrossRefPubMedGoogle Scholar
  18. 18.
    Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67:10804–12.CrossRefPubMedGoogle Scholar
  19. 19.
    Zhao Z, Cheng X, Wang Y, Han R, Li L, Xiang T, et al. Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis. PLoS One. 2014;9:e95884.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Lopez-Bonet E, et al. The anti-diabetic drug metformin suppresses the metastasis-associated protein CD24 in MDA-MB-468 triple-negative breast cancer cells. Oncol Rep. 2011;25:135–40.PubMedGoogle Scholar
  21. 21.
    Wu B, Li S, Sheng L, Zhu J, Gu L, Shen H, et al. Metformin inhibits the development and metastasis of ovarian cancer. Oncol Rep. 2012;28:903–8.PubMedGoogle Scholar
  22. 22.
    Cerezo M, Tichet M, Abbe P, Ohanna M, Lehraiki A, Rouaud F, et al. Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner. Mol Cancer Ther. 2013;12:1605–15.CrossRefPubMedGoogle Scholar
  23. 23.
    Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, et al. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest. 2013;123:630–45.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Madani A, Jozaghi Y, Tabah R, How J, Mitmaker E. Rare metastases of well-differentiated thyroid cancers: a systematic review. Ann Surg Oncol. 2014;22(2):460–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12:245–62.CrossRefPubMedGoogle Scholar
  26. 26.
    Abubaker J, Jehan Z, Bavi P, Sultana M, Al-Harbi S, Ibrahim M, et al. Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab. 2008;93:611–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 2011;71:4403–11.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cai X, Hu X, Cai B, Wang Q, Li Y, Tan X, et al. Metformin suppresses hepatocellular carcinoma cell growth through induction of cell cycle G1/G0 phase arrest and p21CIP and p27KIP expression and downregulation of cyclin D1 in vitro and in vivo. Oncol Rep. 2013;30:2449–57.PubMedGoogle Scholar
  29. 29.
    Dai M, Al-Odaini AA, Fils-Aime N, Villatoro MA, Guo J, Arakelian A, et al. Cyclin D1 cooperates with p21 to regulate TGFbeta-mediated breast cancer cell migration and tumor local invasion. Breast Cancer Res. 2013;15:R49.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Marfil V, Blazquez M, Serrano F, Castell JV, Bort R. Growth-promoting and tumourigenic activity of c-Myc is suppressed by Hhex. Oncogene. 2014. doi: 10.1038/onc.2014.240.PubMedGoogle Scholar
  31. 31.
    Zhou W, Feng X, Ren C, Jiang X, Liu W, Huang W, et al. Over-expression of BCAT1, a c-Myc target gene, induces cell proliferation, migration and invasion in nasopharyngeal carcinoma. Mol Cancer. 2013;12:53.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22.CrossRefPubMedGoogle Scholar
  33. 33.
    Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36:320–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mimeault M, Batra SK. Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol. 2007;18:1605–19.CrossRefPubMedGoogle Scholar
  35. 35.
    Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA. Metformin against TGFbeta-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle. 2010;9:4461–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Lee JH, Kim JH, Kim JS, Chang JW, Kim SB, Park JS, et al. AMP-activated protein kinase inhibits TGF-beta-, angiotensin II-, aldosterone-, high glucose-, and albumin-induced epithelial-mesenchymal transition. Am J Physiol Renal Physiol. 2013;304:F686–97.CrossRefPubMedGoogle Scholar
  37. 37.
    Li L, Han R, Xiao H, Lin C, Wang Y, Liu H, et al. Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res. 2014;20:2714–26.CrossRefPubMedGoogle Scholar
  38. 38.
    Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 2014;74:4783–95.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Endocrinology and MetabolismThe 264 Hospital of PLATaiyuanChina
  2. 2.Department of OncologyPLA General HospitalBeijingChina
  3. 3.Department of Oncology309th Hostital of PLABeijingChina
  4. 4.Department of Nuclear MedicinePeking University First HospitalBeijingChina
  5. 5.Department of RespirationPLA General HospitalBeijingChina
  6. 6.Department of CardiologyGeneral Hospital of the Second ArtilleryBeijingChina

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