Pioglitazone Induces a Proadipogenic Antitumor Response in Mice with PAX8-PPARγ Fusion Protein Thyroid Carcinoma

Abstract

Approximately 35% of follicular thyroid carcinomas harbor a chromosomal translocation that results in expression of a paired box gene 8-peroxisome proliferator-activated receptor γ gene (PPARγ) fusion protein (PPFP). To better understand the oncogenic role of PPFP and its relationship to endogenous PPARγ, we generated a transgenic mouse model that combines Cre-dependent PPFP expression (PPFP;Cre) with homozygous deletion of floxed Pten (PtenFF;Cre), both thyroid specific. Although neither PPFP;Cre nor PtenFF;Cre mice develop thyroid tumors, the combined PPFP;PtenFF;Cre mice develop metastatic thyroid cancer, consistent with patient data that PPFP is occasionally found in benign thyroid adenomas and that PPFP carcinomas have increased phosphorylated AKT/protein kinase B. We then tested the effects of the PPARγ agonist pioglitazone in our mouse model. Pioglitazone had no effect on PtenFF;Cre mouse thyroids. However, the thyroids in pioglitazone-fed PPFP;PtenFF;Cre mice decreased 7-fold in size, and metastatic disease was prevented. Remarkably, pioglitazone caused an adipogenic response in the PPFP;PtenFF;Cre thyroids characterized by lipid accumulation and the induction of a broad array of adipocyte PPARγ target genes. These data indicate that, in the presence of pioglitazone, PPFP has PPARγ-like activity that results in trans-differentiation of thyroid carcinoma cells into adipocyte-like cells. Furthermore, the data predict that pioglitazone will be therapeutic in patients with PPFP-positive carcinomas.

Inhibition of Foxp3 in cancer cells induces apoptosis of thyroid cancer cells

“…Indeed, in a mouse model PPARγ insufficiency results in the activation of the nuclear factor-kappaB (NF-κB) signaling pathway, leading to thyroid carcinogenesis (Kato et al, 2006). Application of PPARγ ligands can delay the progression of thyroid carcinogenesis or arrest the growth of thyroid tumors in mice (Dobson et al, 2011;Kato et al, 2006). The results of animal experiments are in line with human studies in which the activation of PPARγ inhibits the growth of thyroid cancer cells (Bonofiglio et al, 2008;Chen et al, 2006;Copland et al, 2006;Klopper et al, 2004).…”

“…Our finding, for the first time, suggests that Foxp3 can negatively regulate PPARγ in thyroid cancer cells. Previous studies have shown that the activity of PPARγ is reduced in thyroid cancer and that the induction or activation of PPARγ can inhibit the growth of thyroid cancer by promoting apoptosis (Bonofiglio et al, 2008;Chen et al, 2006;Copland et al, 2006;Dobson et al, 2011;Kato et al, 2006;Klopper et al, 2004). Therefore, the finding of PPARγ upregulation by Foxp3 shRNA should well suggest that the high expression of Foxp3 observed in PTC and FTC herein may account for the low activity of PPARγ seen in human thyroid cancer, which may help thyroid cancer cells to escape from PPARγ-mediated killing, and contribute to thyroid tumor invasion and resistance to treatment (Cunha et al, 2012;Ugolini et al, 2014).…”

Adipogenesis and epicardial adipose tissue: A novel fate of the epicardium induced by mesenchymal transformation and PPARγ activation

“…Because an allele that conditionally expresses wild-type PPARγ is not available, for this purpose we used a conditional allele that expresses a Pax8-PPARγ fusion protein (PPFP) after recombination; the fusion protein was previously shown to behave like normal PPARγ, including the induction of adipogenic differentiation, in the presence of an appropriate PPARγ ligand (18). We first tested this genetic manipulation in primary cell culture.…”

Pax-8–PPAR-γ fusion protein in thyroid carcinoma

“…However, transgenic mice with thyroid-specific expression of PPFP and thyroid-specific homozygous deletion of Pten develop metastatic thyroid carcinoma. 93 Deletion of Pten was added to the PPFP mouse model because it results in increased phosphorylated (activated) AKT (pAKT), as observed in human PPFP carcinomas. 94 Increased pAKT is common in FTCs in general and is not specific for PPFP carcinomas, 42 and can result from a variety of genetic or epigenetic events.…”