Phenylbutyrate-induced apoptosis and differential expression of Bcl-2, Bax, p53 and Fas in human prostate cancer cell lines

OBJECTIVE: To assess the mechanisms of action of phenylbutyrate (PB), an in vestigational chemotherapeutic agent for prostate cancer (PCa), in apoptosi s induction in PCa cell lines in vitro. STUDY DESIGN: We analyzed the differential expression of different apoptosi s modulators, Bcl-2, Bar, p53 and Fas, for their potential role in PB-induc ed apoptosis using relative quantitative flow cytometry (FCM). Both androge n-dependent (LNCaP) and androgen-independent (C-4-2, PC-3-PF and DU145) hum an PCa cell lines were examined. RESULTS: PB induced apoptosis in PCa cell lines in a dose-dependent manner. Fifty percent apoptosis could be induced by 5-10 mM PB. Bcl-2 was down-reg ulated 30-75% and the Bax:Bcl-2 ratio elevated in apoptotic PCa cell lines regardless of their androgen dependency or p53 status. FCM revealed a heter ogeneous stimulatory effect on the expression of Bax and Bcl-2 in PC3-PF ce lls at 0.5-2.5 mM PB. In a p53-positive cell line (DU145), p53 was represse d by 70% and Fas elevated sixfold with 5-10 mM PB. CONCLUSION: Our data show that PB-induced PCa apoptosis is associated with the relative repression of Bcl-2 and with up-regulation of Bar and Fas prot eins and that this PB-induced apoptosis is independent of p53 and androgen- dependency status of PCa cell lines.