Effect of metformin on growth of differentiated thyroid cells and thyroid carcinoma cells and their derived cancer stem cells
Year: 2012
Type: dissertation
Abstract: Insulin resistance and consecutive hyperinsulinemia and are the major reasons for a higher prevalence of several cancer entities in type 2 diabetes mellitus and obesity. Insulin exerts its growth-promoting effect via activation of insulin receptor- and insulin-like growth factor (IGF) receptor-dependent signaling. Metformin, an oral anti-diabetic drug, exerts a growth-inhibitory effect by reducing hyperinsulinemia and by a direct cellular action. This dual mode of metformin action is the rationale to consider metformin as a potential drug for adjuvant anti-cancer therapy. The aim of the present work was (1) to identify whether metformin exerts an anti-mitogenic effect on differentiated human thyroid cells and on thyroid carcinoma cells, and to elucidate the underlying mechanism at the cellular level, (2) to prove that metformin targets cancer stem cells in a doxorubicin-resistant anaplastic thyroid carcinoma cell line which are enriched with cancer stem cells, (3) to investigate the effect of metformin on insulin-mediated cell growth, and to find out if metformin inhibits growth by activation of the AMPK pathway, and if it antagonizes the growth stimulatory effect of insulin by inhibition of MAP kinase pathway, (4) to detect whether metformin is capable of amplifying the anti-mitogenic effect of chemotherapeutic agents such as doxorubicin and cisplatin on undifferentiated thyroid carcinoma cells. The study was performed in differentiated human thyroid cells, anaplastic thyroid carcinoma cells, a doxorubicin-resistant thyroid carcinoma cell line and thyroid cancer stem cells. The anti-mitogenic effect of metformin was studied in thyroid cells derived from goiters and in thyroid carcinoma cell lines by analysis of cell growth, cell cycle progression and apoptosis. Furthermore, the influence of pretreatment with insulin or with chemotherapeutic agents on metformin-induced growth inhibition was investigated in thyroid carcinoma cells, in a doxorubicin-resistant thyroid carcinoma cell line and in derived carcinoma stem cells. This work demonstrated that metformin exerted an anti-mitogenic effect on differentiated human thyroid cells and on thyroid carcinoma cells by inhibition of cell cycle progression and induction of apoptosis. Metformin inhibited growth by activation of the AMPK pathway, antagonized the growth stimulatory effect of insulin by inhibition of MAP kinase pathway and inhibited clonal cell growth and thyroid cancer sphere formation, a hallmark of cancer stem cells. Furthermore, metformin amplified the anti-mitogenic effect of chemotherapeutic agents as doxorubicin and cisplatin on undifferentiated thyroid carcinoma cells. Remarkably, this anti-proliferative effect was also observed in doxorubicin-resistant thyroid carcinoma cell line. The growth-inhibitory effect of metformin was, however, not restricted to undifferentiated thyroid carcinoma cells but was also demonstrated in thyroid carcinoma stem cells. In conclusion, metformin markedly diminished growth stimulation by insulin and showed a cumulative anti-mitogenic effect to chemotherapeutics agents. Therefore, our results suggest this drug as adjuvant treatment for undifferentiated thyroid cancer in type 2 diabetic patients and obese patients with hyperinsulinemia.
Author: Chen, Guofang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1513319051