Role of Peroxisome Proliferator-Activated Receptor γ and Its Ligands in Non-Neoplastic and Neoplastic Human Urothelial Cells

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and is expressed in several types of tissue. Although PPARgamma reportedly is expressed in normal urothelium, its function is unknown. We examined the expression of PPARgamma in normal urothelium and bladder cancer in an attempt to assess its functional role. Immunohistochemical staining revealed normal urothelium to express PPARgamma uniformly. All low-grade carcinomas were positive either diffusely or focally, whereas staining was primarily focal or absent in high-grade carcinomas. A nonneoplastic urothelial cell line (1T-1), a low-grade (RT4) carcinoma cell line, and two high-grade (T24 and 253J) carcinoma cell lines in culture expressed PPARgamma mRNA and protein. Luciferase assay indicated that PPARgamma was functional. PPARgamma ligands (15-deoxy-Delta(12,14)-prostaglandin J(2), troglitazone and pioglitazone) suppressed the growth of nonneoplastic and neoplastic urothelial cells in a dose-dependent manner. However, neoplastic cells were more resistant than were nonneoplastic cells. Failure to express PPARgamma or ineffective transcriptional activity may be some of the mechanisms responsible for resistance to the inhibitory action of PPARgamma ligands.

Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis

“…Europe and North America have the highest incidence of bladder cancer, with a higher incidence in those with diabetes [1,2]. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear transcription factor which, in addition to being expressed in normal urothelium, is overexpressed in bladder tumours [3,4]. Pioglitazone and rosiglitazone are thiazolidinediones (TZDs) which act as PPARγ agonists and are used in the treatment of type 2 diabetes.…”

Inhibition of Bladder Tumor Growth by 1,1-Bis(3′-Indolyl)-1-(p-Substitutedphenyl)Methanes: A New Class of Peroxisome Proliferator-Activated Receptor γ Agonists

“…PPARg is highly expressed in tumor samples from different sites, and, in one study, wild-type PPARg mRNA was observed in multiple tumors and in 34 hematopoietic cancer cell lines as well as several lung (10), colon (10), duodenal (1), prostate (5), breast (4), and glioblastoma (2) cell lines (13). PPARg has also been detected in bladder tumors and bladder cancer cell lines (14)(15)(16)(17) and is expressed in the epithelium of the bladder but not surrounding smooth muscle or interstitium (15). PPARg is an excellent target for cancer chemotherapy not only because of its elevated expression in tumors but also because PPARg activation results in decreased cell proliferation, decreased G 0 -G 1 to S phase progression, increased differentiation, and apoptosis (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

Novel high-affinity PPARγ agonist alone and in combination with paclitaxel inhibits human anaplastic thyroid carcinoma tumor growth via p21WAF1/CIP1

“…These findings are in keeping with the suggestion that PPARg acts as a tumor suppressor gene (Nakajima et al, 2001;Smith et al, 2001;Koeffler, 2003). Mechanisms of PPARg-mediated antitumor activity by Tzds demonstrated experimentally include induction of cellular differentiation (Elstner et al, 1998;Guan et al, 1999;Kitamura et al, 1999;Chang and Szabo, 2002;Kawa et al, 2002), promotion of cell cycle arrest (Brockman et al, 1998;Kitamura et al, 1999;Motomura et al, 2000;Itami et al, 2001;Koga et al, 2001;Nakashiro et al, 2001;Takashima et al, 2001;Yin et al, 2001;Kawa et al, 2002;Hong et al, 2004;Rumi et al, 2004;Chen and Harrison, 2005), antiangiogenic effects (reviewed in Alarcon de la Lastra et al, 2004) and induction of apoptosis (Elstner et al, 1998;Kubota et al, 1998;Chang and Szabo, 2000;Tsubouchi et al, 2000;Eibl et al, 2001;Takashima et al, 2001;Yang and Frucht, 2001;Lovekamp-Swan and Chaffin, 2005;Yuan et al, 2005).…”