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

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