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This version published online on June 15, 2006
Endocrinology, doi:10.1210/en.2005-1610
A more recent version of this article appeared on September 1, 2006
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*Compound via MeSH
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*Thyroid Cancer

Submitted on December 19, 2005
Accepted on June 6, 2006

PPAR-{gamma} AGONISTS INDUCE PARTIAL REVERSION OF EPITHELIAL-MESENCHYMAL TRANSITION IN ANAPLASTIC THYROID CANCER CELLS

Aurora Aiello, Giuseppe Pandini, Francesco Frasca, Enrico Conte, Antonella Murabito, Antonella Sacco, Marco Genua, Riccardo Vigneri, and Antonino Belfiore*

From: Dipartimento di Medicina Clinica e Sperimentale, Cattedra di Endocrinologia, University of Catanzaro, 88100 Catanzaro, Italy - Dipartimento di Scienze Biomediche, University of Catania, 95125 Catania, Italy - Dipartimento di Medicina Interna e Medicine Specialistiche, Cattedra di Endocrinologia, University of Catania, Ospedale Garibaldi, 95123, Catania, Italy

* To whom correspondence should be addressed. E-mail: belfiore{at}unicz.it.

Anaplastic thyroid cancer (2) is an extremely aggressive tumor characterized by marked epithelial mesenchymal transition, which leads, almost invariably, to death. PPAR-{gamma} agonists have recently emerged as potential antineoplastic drugs.

To establish whether ATC could be a target of PPAR-{gamma} agonists we first examined PPAR-{gamma} protein expression in a panel of six ATC cell lines and then studied the biologic effects of two PPAR-{gamma} agonists, ciglitazone and rosiglitazone, that belong to the class of thiazolidonediones (3).

PPAR-{gamma} 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 cdk inhibitors p21cip1 and p27kip1, a decrease of cyclin D1 and inactivation of Rb protein. Rosiglitazone-induced apoptosis was associated with a decrease of Bcl-XL expression and caspase 3/7 activation. Moreover, rosiglitazone antagonized IGF-I biological effects by up-regulating PTEN with subsequent inhibition of the PI3K/Akt signaling pathway. Finally, rosiglitazone increased the expression of thyroid specific differentiation markers.

In conclusions, these data suggest that PPAR-{gamma} agonists induce a partial reversion of the epithelial mesenchymal transition in ATC cells by multiple mechanisms. PPAR-{gamma} agonists may, therefore, have a role in the multimodal therapy currently used to slow down ATC growth and dissemination.
Key words: PPAR{gamma} agonists • Thyroid cancer • IGF system • PTEN




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