Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor characterized by marked epithelial mesenchymal transition, which leads, almost invariably, to death. Peroxisomal proliferator-activated receptor (PPAR)-Î³ agonists have recently emerged as potential antineoplastic drugs. To establish whether ATC could be a target of PPARÎ³ agonists, we first examined PPARÎ³ protein expression in a panel of six ATC cell lines and then studied the biologic effects of two PPARÎ³ agonists, ciglitazone and rosiglitazone, that belong to the class of thiazolidonediones. PPARÎ³ protein was present and functional in all ATC cell lines. Both ciglitazone and rosiglitazone showed complex biological effects in ATC cells, including inhibition of anchorage-dependent and -independent growth and migration, and increased apoptosis rate. Rosiglitazone-induced growth inhibition was associated with cell cycle arrest and changes in cell cycle regulators, such as an increase of cyclin-dependent kinases inhibitors p21cip1 and p27 kip1, a decrease of cyclin D1, and inactivation of Rb protein. Rosiglitazone-induced apoptosis was associated with a decrease of Bcl-X L expression and caspase-3 and -7 activation. Moreover, rosiglitazone antagonized IGF-I biological effects by up-regulating phosphatase and tensin homolog deleted from chromosome 10 with subsequent inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway. Finally, rosiglitazone increased the expression of thyroid-specific differentiation markers. In conclusions, these data suggest that PPARÎ³ agonists induce a partial reversion of the epithelial mesenchymal transition in ATC cells by multiple mechanisms. PPARÎ³ agonists may, therefore, have a role in the multimodal therapy currently used to slow down ATC growth and dissemination. Copyright Â© 2006 by The Endocrine Society.
|Titolo:||Peroxisomal proliferator-activated receptor-Î³ agonists induce partial reversion of epithelial-mesenchymal transition in anaplastic thyroid cancer cells|
BELFIORE, Antonino (Corresponding)
|Data di pubblicazione:||2006|
|Appare nelle tipologie:||1.1 Articolo in rivista|