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

Abstract

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)-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. 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 cyclin-dependent kinases inhibitors p21(cip1) 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 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.

Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion

“…The role oncogenes play in initiation of EMT-related changes and the roles of other EMT-related proteins, including osteopontin, RUNX2, and fibronectin 1 remain to be defined; however, recent evidence from in vitro models demonstrate that RET/PTC and BRAF influence the invasive capacity of benign rat thyroid cells through both PI3 kinase and ERK signaling, in part, through regulation of matrix metalloproteinases and osteopontin (16,32). Whereas we have studied a small panel of thyroid cancer cell lines, studies from other thyroid (33,34) and nonthyroid cancer cell systems support a role for incomplete or complete EMT as common endpoints in tumor progression (35). Additional studies are needed to determine the role of specific EMT regulators, such as vimentin, in a larger number of cancer cell lines.…”

Antineoplastic effect of iodine and iodide in dimethylbenz[a]anthracene-induced mammary tumors: association between lactoperoxidase and estrogen-adduct production

“…These antitumor effects have also been attributed to PPARg activation. There is evidence that PPARg agonists promote cell redifferentiation, which is reflected in the upregulation of specific differentiation markers (NIS, TSH receptor, LPO, and thyroglobulin) and downregulation of a dedifferentiation marker (CD97) in thyroid cancer (Park et al 2005, Aiello et al 2006. Additional experiments are required to confirm this hypothesis with respect to breast cancer.…”

Alternative Medical Treatment for Radioiodine-Refractory Thyroid Cancers

“…In an initial study, Karger et al reported that mRNA for PPARγ is downregulated in papillary thyroid cancer cells [37], and Chung et al reported that troglitazone inhibits growth of anaplastic thyroid cancer cells [38]. Similar results have been consistently observed in other anaplastic or dedifferentiated thyroid cancer cells, that is, various thiazolinediones induce cell growth inhibition, cell cycle arrest, and apoptosis [39][40][41]. This activity is explicitly correlated with PPARγ activation because PPARγ-lacking thyroid cancer cells did not demonstrate such effects, and restoration of PPARγ resulted in restoration of response to thiazolinediones [39,42].…”

“…This activity is explicitly correlated with PPARγ activation because PPARγ-lacking thyroid cancer cells did not demonstrate such effects, and restoration of PPARγ resulted in restoration of response to thiazolinediones [39,42]. Interestingly, activation of apoptosis by thiazolinediones was not related to p53, but to p21 or p27 [38,39,41]. Besides growth inhibition and apoptosis activation, PPARγ agonists induce differentiation of thyroid cancer cells.…”