Effect of Metformin on the Medullary Thyroid Cancer Cells



Background. Medullary thyroid cancer (MTC) is associated with activation of mTOR signaling
pathways. Recent studies showed that the anti-diabetic agent metformin decreases proliferation of cancer cells
through AMPK-dependent inhibition of mTOR.
The objective of current study — assessment of the effect of metformin on MTC cells.
Materials and Methods. Performed growth, viability, migration and resistance to anoikis assays using two
MTC-derived cell lines (TT and MZ-CRC-1). Expressions of molecular targets of metformin were examined in
MTC cell lines and in 14 human MTCs tissue samples.
Results. We found that metformin inhibited growth and decreased expression of Cyclin D1 in MTC cells. Treatment
with metformin was associated with inhibition of mTOR/p70S6K/pS6 signaling and with down-regulation of
pERK in both TT and MZ-CRC-1 cells. Metformin had no significant effects on pAKT in the cell lines examined.
Metformin inducible AMPK activation was noted only in TT cells. Treatment with AMPK inhibitor (Compound C)
or AMPK silencing did not prevent growth-inhibitory effects of metformin in TT cells. Metformin had no effect on MTC cell migration, but reduced the ability of cells to form multi-cellular spheroids in non adherent conditions.
Immunostaining of human MTC showed over-expression of Cyclin D1 in all tumors compared to corresponding normal tissue. Activation of mTOR/p70S6K was detected in 8/14 (57.1 %) of examined tumors.
Conclusions. Together these findings indicate that growth inhibitory effects in MTC cells are associated with
down-regulation of both mTOR/6SK and pERK signaling pathways. Expression of metformin’s molecular targets
in human MTC cells suggests its potential utility for the treatment of MTC in patients.


metformin; anoikis; medullary thyroid cancer

Full Text:



Astrinidis A., Henske E.P. Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease // Oncogene. — 2005. — Vol. 24. — P. 7475-7481.

Ben Sahra I., Laurent K., Loubat A., Giorgetti-Peraldi S., Colosetti P., Auberger P., Tanti J.F., Le Marchand-Brustel Y., Bost F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level // Oncogene. — 2008. — Vol. 27. — P. 3576-3586.

Ben Sahra I., Le Marchand-Brustel Y., Tanti J.F., Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? // Mol. Cancer Ther. — 2010. — Vol. 9. — P. 1092-1099.

Cabanillas M.E., Waguespack S.G., Bronstein Y., Williams M.D., Feng L., Hernandez M., Lopez A., Sherman S.I., Busaidy N.L. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M.D. Anderson experience // J. Clin. Endocrinol. Metab. — 2010. — Vol. 95. — P. 2588-2595.

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. — Vol. 97. — № 4. — P. 510-520.

Costanzo-Garvey D.L., Pfluger P.T., Dougherty M.K., Stock J.L., Boehm M., Chaika O., Fernandez M.R., Fisher K., Kortum R.L., Hong E.G. et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity // Cell Metab. — 2009. — Vol. 10. — P. 366-378.

De Groot J.W., Links T.P., Plukker J.T., Lips C.J., Hofstra R.M. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors // Endocr. Rev. — 2006. — Vol. 27. — P. 535-560.

Dell’Aglio D.M., Perino L.J., Kazzi Z., Abramson J., Schwartz M.D., Morgan B.W. Acute metformin overdose: exami-ning serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature // Ann. Emerg. Med. — 2009. — Vol. 54. — P. 818-823.

Dowling R.J., Zakikhani M., Fantus I.G., Pollak M., Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells // Cancer Res. — 2007. — Vol. 67. — P. 10804-10812.

Drosten M., Hilken G., Bockmann M., Rodicker F., Mise N., Cranston A.N., Dahmen U., Ponder B.A., Putzer B.M. Role of MEN2A-derived RET in maintenance and proliferation of medullary thyroid carcinoma // J. Natl Cancer Inst. — 2004. — Vol. 96. — P. 1231-1239.

El-Mir M.Y., Nogueira V., Fontaine E., Averet N., Rigoulet M., Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I // J. Biol. Chem. — 2000. — Vol. 275. — P. 223-228.

Faggiano A., Ramundo V., Dicitore A., Castiglioni S., Borghi M.O., Severino R., Ferolla P., Crino L., Abbruzzese A., Sperlongano P. et al. Everolimus is an active agent in medullary thyroid cancer: a clinical and in vitro study // J. Cell. Mol. Med. — 2012. — Vol. 16. — P.1563-1572.

Fukazawa H., Noguchi K., Murakami Y., Uehara Y. Mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitors restore anoikis sensitivity in human breast cancer cell lines with a constitutively activated extracellular-regulated kinase (ERK) pathway // Mol. Cancer Ther. — 2002. — Vol. 1. — P. 303-309.

Goldstein N.B., Johannes W.U., Gadeliya A.V., Green M.R., Fujita M., Norris D.A., Shellman Y.G. Active N-Ras and B-Raf inhibit anoikis by downregulating Bim expression in melanocytic cells // J. Invest. Dermatol. — 2009. — Vol. 129. — P. 432-437.

Gotlieb W.H., Saumet J., Beauchamp M.C., Gu J., Lau S., Pollak M.N., Bruchim I. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer // Gynecol. Oncol. — 2008. — Vol. 110. — P. 246-250.

Grozinsky-Glasberg S., Rubinfeld H., Nordenberg Y., Gorshtein A., Praiss M., Kendler E., Feinmesser R., Grossman A.B., Shimon I. The rapamycin-derivative RAD001 (everolimus) inhibits cell viability and interacts with the Akt-mTOR-p70S6K pathway in human medullary thyroid carcinoma cells // Mol. Cell. Endocrinol. — 2010. — Vol. 315. — P. 87-94.

Guertin D.A., Sabatini D.M. Defining the role of mTOR in cancer // Cancer Cell. — 2007. — Vol. 12. — P. 9-22.

Hundahl S.A., Fleming I.D., Fremgen A.M., Menck H.R. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns] // Cancer. — 1998. — Vol. 83. — P. 2638-2648.

Jensen K., Patel A., Klubo-Gwiezdzinska J., Bauer A., Vasko V. Inhibition of gap junction transfer sensitizes thyroid cancer cells to anoikis // Endocr. Relat. Cancer. — 2011. — Vol. 18. — P. 613-626.

Lam E.T., Ringel M.D., Kloos R.T., Prior T.W., Knopp M.V., Liang J., Sammet S., Hall N.C., Wakely P.E. Jr., Vasko V.V. et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer // J. Clin. Oncol. — 2010. — Vol. 28. — P. 2323-2330.

Lanzi C., Cassinelli G., Nicolini V., Zunino F. Targeting RET for thyroid cancer therapy // Biochem. Pharmacol. — 2009. — Vol. 77. — P. 297-309.

Luo Z., Zang M., Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth // Future Oncol. — 2010. — Vol. 6. — P. 457-470.

Martin-Castillo B., Vazquez-Martin A., Oliveras-Ferraros C., Menendez J.A. Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena // Cell Cycle. — 2010. — Vol. 9. — P. 1057-1064.

Modigliani E., Cohen R., Campos J.M., Conte-Devolx B., Maes B., Boneu A., Schlumberger M., Bigorgne J.C., Dumontier P., Leclerc L. et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine // Clin. Endocrinol. (Oxf). — 1998. — Vol. 48. — P. 265-273.

Pelizzo M.R., Boschin I.M., Bernante P., Toniato A., Piotto A., Pagetta C., Nibale O., Rampin L., Muzzio P.C., Rubello D. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients // Eur. J. Surg. Oncol. — 2007. — Vol 33. — P. 493-497.

Rapa I., Saggiorato E., Giachino D., Palestini N., Orlandi F., Papotti M., Volante M. Mammalian target of rapamycin pathway activation is associated to RET mutation status in medullary thyroid carcinoma // J. Clin. Endocrinol. Metab. — 2011. — Vol. 96. — P. 2146-2153.

Segouffin-Cariou C., Billaud M. Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway // J. Biol. Chem. — 2000. — Vol. 275. — P. 3568-3576.

Shaw R.J. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth // Acta Physiol. (Oxf). — 2009. — Vol. 196. — P. 65-80.

Shaw R.J., Cantley L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth // Nature. — 2006. — Vol. 441. — P. 424-430.

Sonenberg N., Gingras A.C. The mRNA 5’ cap-binding protein eIF4E and control of cell growth // Curr. Opin. Cell Biol. — 1998. — Vol. 10. — P. 268-275.

Vasko V., Espinosa A.V., Scouten W., He H., Auer H., Liyanarachchi S., Larin A., Savchenko V., Francis G.L., de la Chapelle A. et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion // Proc. Natl Acad. Sci. USA. — 2007. — Vol. 104. — P. 2803-2808.

Vesely J., Havlicek L., Strnad M., Blow J.J., Donella-Deana A., Pinna L., Letham D.S., Kato J., Detivaud L., Leclerc S. et al. Inhibition of cyclin-dependent kinases by purine analogues // Eur. J. Biochem. — 1994. — Vol. 224. — P. 771-786.

Wullschleger S., Loewith R., Hall M.N. TOR signaling in growth and metabolism // Cell. — 2006. — Vol. 124. — P. 471-484.

Zhuang Y., Miskimins W.K. Cell cycle arrest in metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1 // J. Mol. Signal. — 2008. — Vol. 3. — PMC2613390. — 11 p.

Zugasti O., Rul W., Roux P., Peyssonnaux C., Eychene A., Franke T.F., Fort P., Hibner U. Raf-MEK-Erk cascade in anoikis is controlled by Rac1 and Cdc42 via Akt // Mol. Cell Biol. — 2001. — Vol. 21. — P. 6706-6717.

DOI: https://doi.org/10.22141/2224-0721.5.53.2013.84481


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.


© "Publishing House "Zaslavsky", 1997-2017


 Яндекс.МетрикаSeo анализ сайта Рейтинг@Mail.ru