Introduction: It has been demonstrated that mTOR inhibitors have potent anti-proliferative effects in a human Medullary Thyroid Carcinoma (MTC) cell lines. We here explore the possible role of mTOR inhibitors, Everolimus and BEZ235 (which also inhibits the PI3K pathway) on the effects of Insulin-like Growth Factor-1 (IGF-1) in human MTC primary cultures. Aims: To this purpose, 20 MTCs primary cultures, were treated without or with 1 uM Everolimus, 10 nM BEZ235, and/or 50 nM IGF-1. Materials and methods: Cell viability and apoptosis were evaluated after 48 h. p70S6K phosphorylation was evaluated by ELISA. Results: we observed that Everolimus and BEZ235 significantly reduced MTC cell viability, by 20 and 35% respectively, while IGF-1 enhanced cell viability, an effect completely blocked by mTOR inhibitors. Co-incubation with an IGF-1R blocking antibody enhanced the antiproliferative effects of. Everolimus and BEZ235. Caspase activity was enhanced by BEZ235 and reduced by IGF-1, an effect that was attenuated by co-treatment with mTOR inhibitors. Phosphorylation of p70S6K, a down-stream mTOR effector in the PI3K/Akt pathway, was evaluated to assess whether this effect is due to variations in mTOR activity. We observed that IGF-1 enhanced p70S6K phosphorylation, that is reduced by mTOR inhibitors, indicating that IGF-1 exerts its proliferative effects by inducing this pathway. Conclusion: In conclusion, mTOR inhibitors reduced MTCs cell viability by inducing apoptosis, with a mechanism likely involving IGF-1 signalling, suggesting that these drugs might represent a possible medical treatment for persistent/recurrent MTCs.
mTOR inhibitors hamper cell viability in selected human medullary thyroid carcinoma primary cultures
MINOIA, Mariella;ROSSI, Martina;GENTILIN, Erica;MOLE', Daniela;DEGLI UBERTI, Ettore;ZATELLI, Maria Chiara
2012
Abstract
Introduction: It has been demonstrated that mTOR inhibitors have potent anti-proliferative effects in a human Medullary Thyroid Carcinoma (MTC) cell lines. We here explore the possible role of mTOR inhibitors, Everolimus and BEZ235 (which also inhibits the PI3K pathway) on the effects of Insulin-like Growth Factor-1 (IGF-1) in human MTC primary cultures. Aims: To this purpose, 20 MTCs primary cultures, were treated without or with 1 uM Everolimus, 10 nM BEZ235, and/or 50 nM IGF-1. Materials and methods: Cell viability and apoptosis were evaluated after 48 h. p70S6K phosphorylation was evaluated by ELISA. Results: we observed that Everolimus and BEZ235 significantly reduced MTC cell viability, by 20 and 35% respectively, while IGF-1 enhanced cell viability, an effect completely blocked by mTOR inhibitors. Co-incubation with an IGF-1R blocking antibody enhanced the antiproliferative effects of. Everolimus and BEZ235. Caspase activity was enhanced by BEZ235 and reduced by IGF-1, an effect that was attenuated by co-treatment with mTOR inhibitors. Phosphorylation of p70S6K, a down-stream mTOR effector in the PI3K/Akt pathway, was evaluated to assess whether this effect is due to variations in mTOR activity. We observed that IGF-1 enhanced p70S6K phosphorylation, that is reduced by mTOR inhibitors, indicating that IGF-1 exerts its proliferative effects by inducing this pathway. Conclusion: In conclusion, mTOR inhibitors reduced MTCs cell viability by inducing apoptosis, with a mechanism likely involving IGF-1 signalling, suggesting that these drugs might represent a possible medical treatment for persistent/recurrent MTCs.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
