Bacillus Calmette-Guérin induces the expression of peroxisome proliferator-activated receptor gamma in bladder cancer cells.
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 proliferator-activated receptor gamma (PPARgamma) 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. PPARgamma is expressed in normal urothelium and a lack of expression was associated with bladder cancer progression. We analyzed whether PPARgamma is involved in the inhibition of bladder cancer cell survival by BCG. PPARgamma expression in murine MB49 and human T24 bladder cancer cells was evaluated employing immunofluorescence and immunohistochemistry 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 PPARgamma 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-Delta12,14 prostaglandin J2 (15-d-PGJ2) but not rosiglitazone (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 PPARgamma 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 PPARgamma-independent pathway since it was not antagonized by BADGE. Thus, our results show that BCG induces functional PPARgamma in bladder tumor cells in vivo and in vitro, being these receptors intrinsically involved in the antitumor activity of BCG.
Lodillinsky
Catalina
C
Angel H. Roffo Institute of Oncology, University of Buenos Aires, CP1417 DTB, Buenos Aires, Argentina.
Umerez
María Sol
MS
Jasnis
María Adela
MA
Casabé
Alberto
A
Sandes
Eduardo
E
Eiján
Ana María
AM
D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
D047495:PPAR gamma; D009569:Nitric Oxide