Peroxisomal Proliferator-Activated Receptor-γ Agonists Induce Partial Reversion of Epithelial-Mesenchymal Transition in Anaplastic Thyroid Cancer Cells

• Published in: Endocrinology (Philadelphia) 2006-09, Vol.147 (9), p.4463-4475
• Main Authors: Aiello, Aurora, Pandini, Giuseppe, Frasca, Francesco, Conte, Enrico, Murabito, Antonella, Sacco, Antonella, Genua, Marco, Vigneri, Riccardo, Belfiore, Antonino
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Agonists; AKT protein; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Apoptosis; Apoptosis - drug effects; Bcl-x protein; bcl-X Protein - analysis; Biological and medical sciences; Biological effects; Cancer; Carcinoma - pathology; Caspase 3; Caspase 7; Caspases - metabolism; Cell cycle; Cell Cycle - drug effects; Cell differentiation; Cell Division - drug effects; Cell Line, Tumor; Cell migration; Chromosome 10; Cyclin D1; Cyclin D1 - analysis; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - analysis; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-dependent kinases; Endocrinopathies; Epithelial Cells - pathology; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; GTP-binding protein; Humans; Inactivation; Insulin-like growth factor I; Insulin-Like Growth Factor I - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - analysis; Kinases; Luciferases - genetics; Malignant tumors; Medical sciences; Mesoderm - pathology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Peroxisome proliferator-activated receptors; Phosphorylation; PPAR gamma - agonists; PPAR gamma - genetics; Proteins; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - genetics; PTEN protein; Receptors; Retinoblastoma protein; Retinoblastoma Protein - analysis; RNA, Small Interfering - pharmacology; Rosiglitazone; Signal transduction; Tensin; Thiazolidinediones - pharmacology; Thyroid; Thyroid cancer; Thyroid Neoplasms - pathology; Thyroid. Thyroid axis (diseases); Transfection; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2005-1610

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)-γ agonists have recently emerged as potential antineoplastic drugs. To establish whether ATC could be a target of PPARγ agonists, we first examined PPARγ protein expression in a panel of six ATC cell lines and then studied the biologic effects of two PPARγ agonists, ciglitazone and rosiglitazone, that belong to the class of thiazolidonediones. PPARγ 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 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 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 PPARγ agonists induce a partial reversion of the epithelial mesenchymal transition in ATC cells by multiple mechanisms. PPARγ agonists may, therefore, have a role in the multimodal therapy currently used to slow down ATC growth and dissemination.