Troglitazone, the Peroxisome Proliferator-Activated Receptor-γ Agonist, Induces Antiproliferation and Redifferentiation in Human Thyroid Cancer Cell Lines

Abstract

Troglitazone is a potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma) that is a ligand-activated transcription factor regulating cell differentiation and growth. PPARgamma may play a role in thyroid carcinogenesis since PAX8-PPARgamma1 chromosomal translocations are commonly found in follicular thyroid cancers. We investigated the antiproliferative and redifferentiation effects of troglitazone in 6 human thyroid cancer cell lines: TPC-1 (papillary), FTC-133, FTC-236, FTC-238 (follicular), XTC-1 (Hürthle cell), and ARO82-1 (anaplastic) cell lines. PPARgamma was expressed variably in these cell lines. FTC-236 and FTC-238 had a rearranged chromosome at 3p25, possibly implicating the involvement of the PPARgamma encoding gene whereas the other cell lines did not. Troglitazone significantly inhibited cell growth by cell cycle arrest and apoptotic cell death. PPARgamma overexpression did not appear to be a prerequisite for a response to treatment with troglitazone. Troglitazone also downregulated surface expression of CD97, a novel dedifferentiation marker, in FTC-133 cells and upregulated sodium iodide symporter (NIS) mRNA in TPC-1 and FTC-133 cells. Our investigations document that human thyroid cancer cell lines commonly express PPARgamma, but chromosomal translocations involving PPARgamma are uncommon. Troglitazone, a PPARgamma agonist, induced antiproliferation and redifferentiation in thyroid cancer cell lines. PPARgamma agonists may therefore be effective therapeutic agents for the treatment of patients with thyroid cancer that fails to respond to traditional treatments.

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.…”

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

“…As the discovery of the PAX8-PPARg fusion gene in human follicular thyroid carcinoma and the demonstration of loss of PPARg transcription activity in the PAX8-PPARg fusion gene , there has been great interest in understanding the role of PPARg in the development and progression of follicular thyroid carcinoma. In vitro cell-based studies have shown that troglitazone induces antiproliferation and apoptosis in several human thyroid cell lines (Ohta et al, 2001;Park et al, 2005), but TRb PV/PV mice provide the first opportunity to address this question in vivo. The present study showed that treatment of TRb PV/PV mice in vivo with PPARg ligands inhibited thyrocyte proliferation and induced apoptosis.…”

Dysregulation of secretion of CXC α-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-γ agonists

“…Agonists of PPARg had an antiproliferative action in six cell lines, originated from patients with papillary thyroid cancer which expressed PPARg, inducing apoptosis (Ohta et al 2001), significantly inhibited tumor growth and prevented distant metastasis of thyroid cancer in nude mice. Furthermore, it has been shown that troglitazone significantly inhibited cell growth by cell cycle arrest and apoptotic cell death (Park et al 2005). More recently, we have shown in primary cultured human anaplastic and papillary dedifferentiated thyroid cancers cells the antiproliferative effect of PPARg agonists thiazolidinediones (TZDs; Antonelli et al 2008a,b).…”