Lodillinsky 6_9

Bacillus Calmette-Guérin (BCG) is considered to be one of the most effective treatments for superficial and in situ bladder cancer. The exact mechanism of the antitumor activity of BCG is not completely understood. Peroxisome proliferatoractivated receptor gamma (PPARÁ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that is involved in cell growth and differentiation as well as inflammatory processes. PPARÁ is expressed in normal urothelium and a lack of expression was associated with bladder cancer progression. We analyzed whether PPARÁ is involved in the inhibition of bladder cancer cell survival by BCG. PPARÁ expression in murine MB49 and human T24 bladder cancer cells was evaluated employing immunofluorescence and inmunohistochemistry techniques. In vitro cell viability and nitric oxide (NO) production was evaluated by using MTS and Griess reagent respectively. Our results show that BCG induced the cytoplasmatic expression of PPARÁ in bladder tumor cells in vitro and in vivo. BADGE, antagonist of this receptor, abrogated in vitro BCG-mediated cell cytotoxicity. Natural agonist 15-deoxy-Δ12,14 prostaglandin J2 (15-d-PGJ2) but not rosiglitazona (RO), a synthetic agonist, induced in vitro inhibition of cell viability of both cancer cell lines and the effect was partially reversed by BADGE. We also determined whether the activation of PPARÁ could inhibit NO production, which is considered a survival factor for bladder tumor cells. Both 15-d-PGJ2 and RO significantly inhibited the NO production in T24 and MB49 cells by PPARÁindependent pathway since it was not antagonized by BADGE. Thus, our results show that BCG induces functional PPARÁ in bladder tumor cells in vivo and in vitro, being these receptors intrinsically involved in the antitumor activity of BCG.