Bacillus Calmette-Guérin induces the expression of peroxisome proliferator-activated receptor gamma in bladder cancer cells

Abstract

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.

Peroxisome proliferator-activated receptor γ in bladder cancer: A promising therapeutic target

“…BADGE also directly reversed BCG-mediated cell death, confirming that PPARγ is involved in BCG cytotoxic activity. 95 These findings suggest BCG has the ability to induce functional PPARγ which can respond only to the endogenous ligand. Moreover, the promising mechanism of Bacillus Calmette-Guerin (BCG) treating superficial bladder carcinoma has been investigated.…”

“…94 Recent studies have demonstrated that in bladder tumor cells, which PPARγ expression was weak or absent, standard therapy with Bacillus Calmette-Guerin therapy (BCG), induced cytoplasmic expression of PPARγ. 95 Additionally, it is noteworthy that the inhibition of cell viability by 15-d-PGJ 2 was only detected in the presence of BCG, and the effect of 15-d-PGJ 2 was PPARγ-dependent, since BADGE, a specific PPARγ antagonist, reversed the BCG-mediated cell cytotoxicity. BADGE also directly reversed BCG-mediated cell death, confirming that PPARγ is involved in BCG cytotoxic activity.…”

Inducible Nitric Oxide Synthase and PPARγ are Involved in Bladder Cancer Progression

“…This is in accord with previous results showing that PPAR␥ expression is associated with the inhibition of tumor growth induced by BCG immunotherapy, a conventional treatment to prevent the recurrence and progression of NMI bladder tumors with high histological grade. 29 As mentioned, there are discrepancies in interpreting the role of PPAR␥ in human bladder tumors. In addition to variations in methodology and reagents in each study, the chosen cutoff determining whether tumors were considered positive or negative had an important role in interpreting the results.…”

“…21,22 Results from our laboratory showed that BCG induces not only the inhibition of in vivo and in vitro tumor growth but also NO production 30 and PPAR␥ expression. 29 NO inhibition improved the murine tumor regression induced by BCG in vivo. 30 In vitro the endogenous agonist of PPAR␥ 15-d-PGJ2 inhibited cancer cell viability and NO production when used in the presence of BCG.…”

Th1 Cytokine-Secreting Recombinant Bacillus Calmette-Guérin: Prospective Use in Immunotherapy of Bladder Cancer

“…Although there is a discrepancy with regard to its actual role in bladder cancer, it appears that the lack of PPARγ expression is associated with bladder cancer progression. Recent studies have demonstrated that BCG could directly induce PPARγ in UCC both in vitro and in vivo, which may contribute to the antitumor activity of BCG (Lodillinsky et al, 2006).…”