Abstract
Peroxisome proliferator‐activated receptor γ (PPARγ) agonists cause cell death in several types of cancer cells. The aim of this study was to examine the effects of two PPARγ agonists, ciglitazone and 15‐deoxy‐Δ ^12,14^‐prostaglandin J2 (15dPGJ2), on the survival of thyroid carcinoma CGTH W‐2 cells. Both ciglitazone and 15dPGJ2 decreased cell viability in a time‐ and dose‐dependent manner. Cell death was mainly due to apoptosis, with a minor contribution from necrosis. Increased levels of active caspase 3, cleaved poly (ADP‐ribose) polymerase (PARP), and cytosolic cytochrome‐c were noted. In addition, ciglitazone and 15dPGJ2 induced detachment of CGTH W‐2 cells from the culture substratum. Both the protein levels and immunostaining signals of focal adhesion (FA) proteins, including vinculin, integrin β1, focal adhesion kinase (FAK), and paxillin were decreased after PPARγ agonist treatment. Meanwhile, reduced phosphorylation of FAK and paxillin was noted. Furthermore, PPARγ agonists induced expression of protein tyrosine phosphatase‐PEST (PTP‐PEST), and of phosphatase and tensin homologue deleted on chromosome ten (PTEN). The upregulation of these phosphatases might contribute to the dephosphorylation of FAK and paxillin, since pre‐treatment with orthovanadate prevented PPARγ agonist‐induced dephosphorylation of FAK and paxillin. Perturbation of CGTH W‐2 cells with anti‐integrin β1 antibodies induced FA disruption and apoptosis in the same cells, thus the downregulation of integrin β1 by PPARγ agonists resulted in FA disassembly and might induce apoptosis via anoikis. Our results suggested the presence of crosstalk between apoptosis and integrin‐FA signaling. Moreover, upregulation and activation of PTEN was correlated with reduced phosphorylation of Akt, and this consequence disfavored cell survival. In conclusion, PPARγ agonists induced apoptosis of thyroid carcinoma cells via the cytochrome‐c caspase 3 and PTEN‐Akt pathways, and induced necrosis via the PARP pathway. J. Cell. Biochem. 98: 1021–1035, 2006. © 2006 Wiley‐Liss, Inc.