Effects of PPARgamma agonists on cell survival and focal adhesions in a Chinese thyroid carcinoma cell line.
JOURNAL OF CELLULAR BIOCHEMISTRY(2006)
摘要
Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists cause cell death in several types of cancer cells. The aim of this study was to examine the effects of two PPAR gamma agonists, ciglitazone and 15-deoxy-Delta(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 beta 1, focal adhesion kinase (FAK), and paxillin were decreased after PPAR gamma agonist treatment. Meanwhile, reduced phosphorylation of FAK and paxillin was noted. Furthermore, PPAR gamma 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 pretreatment with orthovanadate prevented PPAR gamma agonist-induced dephosphorylation of FAK and paxillin. Perturbation of CGTH W-2 cells with anti-integrin beta 1 antibodies induced FA disruption and apoptosis in the same cells, thus the downregulation of integrin beta 1 by PPAR beta 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, PPAR gamma 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. (c) 2006 Wiley-Liss, Inc.
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关键词
PPAR gamma agonists,necrosis,apoptosis,focal adhesion
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