Activation Of Ppar Gamma And Inhibition Of Cell Proliferation Reduces Key Proteins Associated With The Basal Subtype Of Bladder Cancer In As3+-Transformed Urotsa Cells

Environmental exposure to arsenite (As3+) has a strong association with the development of human urothelial cancer (UC) and is the 5(th)most common cancer in men and the 12(th)most common cancer in women. Muscle invasive urothelial cancer (MIUC) are grouped into basal or luminal molecular subtypes based on their gene expression profile. The basal subtype is more aggressive and can be associated with squamous differentiation, characterized by high expression of keratins (KRT1, 5, 6, 14, and 16) and epidermal growth factor receptor (EGFR) within the tumors. The luminal subtype is less aggressive and is predominately characterized by elevated gene expression of peroxisome proliferator-activated receptor- gamma (PPAR gamma) and forkhead box protein A1 (FOXA1). We have previously shown that As3+-transformed urothelial cells (As-T) exhibit a basal subtype of UC expressing genes associated with squamous differentiation. We hypothesized that the molecular subtype of the As-T cells could be altered by inducing the expression of PPAR gamma and/or inhibiting the proliferation of the cells. Non-transformed and As-T cells were treated with Troglitazone (TG, PPARG agonist, 10 mu M), PD153035 (PD, an EGFR inhibitor, 1 mu M) or a combination of TG and PD for 3 days. The results obtained demonstrate that treatment of the As-T cells with TG upregulated the expression of PPAR gamma and FOXA1 whereas treatment with PD decreased the expression of some of the basal keratins. However, a combined treatment of TG and PD resulted in a consistent decrease of several proteins associated with the basal subtype of bladder cancers (KRT1, KRT14, KRT16, P63, and TFAP2A). Our data suggests that activation of PPAR gamma while inhibiting cell proliferation facilitates the regulation of genes involved in maintaining the luminal subtype of UC.In vivoanimal studies are needed to address the efficacy of using PPAR gamma agonists and/or proliferation inhibitors to reduce tumor grade/stage of MIUC.