Apoptotic effect of the selective PPAR β/δ agonist GW501516 in invasive bladder cancer cells

AbstractGW501516 is a selective and high-affinity synthetic agonist of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). This molecule promoted the inhibition of proliferation and apoptosis in few cancer cell lines, but its anticancer action has never been investigated in bladder tumor cells. Thus, this study was undertaken to determine whether GW501516 had antiproliferative and/or apoptotic effects on RT4 and T24 urothelial cancer cells and to explore the molecular mechanisms involved. Our results indicated that, in RT4 cells (derived from a low-grade papillary tumor), GW501516 did not induce cell death. On the other hand, in T24 cells (derived from an undifferentiated high-grade carcinoma), this PPARβ/δ agonist induced cytotoxic effects including cell morphological changes, a decrease of cell viability, a G2/M cell cycle arrest, and the cell death as evidenced by the increase of the sub-G1 cell population. Furthermore, GW501516 triggered T24 cell apoptosis in a caspase-dependent mann er including both extrinsic and intrinsic apoptotic pathways through Bid cleavage. In addition, the drug led to an increase of the Bax/Bcl-2 ratio, a mitochondrial dysfunction associated with the dissipation of ΔΨm, and the release of cytochrome c from the mitochondria to the cytosol. GW501516 ind uced also ROS generation which was not responsible for T24 cell death since NAC did not rescue cells upon PPARβ/δ agonist exposure. For the first time, our data highlight the capacit...

Source: Tumor Biology - September 15, 2016 Category: Cancer & Oncology Source Type: research