Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation

BACKGROUND. We previously reported that FTY720, a metabolite from Isaria si nclairii, induced some cancer Tells to undergo apoptosis, and that FTY720-i nduced apoptosis was not related to Fas-antigens. In this study we investig ated whether FTY720 was able to induce apoptosis in an androgen-independent prostate cancer cell Line, DU145, which is not only resistant to androgen- withdrawal-induced apoptosis but also Fas- and TNF-alpha-mediated apoptosis . METHODS. Cell survival and morphological change were examined and apoptosis was confirmed by DNA isolation and analysis of DNA fragmentation. Caspase activation was studied by using anti-caspase-1 and anti-caspase-3 antibodie s. To determine whether caspase activation is central to FTY720-induced apo ptosis, caspase inhibitor was added to the media 24 hr prior to the additio n of FTY720. RESULTS. We found that FTY720 rapidly induced apoptosis in DU145 cells, and that caspase-3 was activated during FTY720-induced apoptosis. In contrast, normal human prostate stromal cells were resistant to FTY720. Furthermore, FTY720-induced apoptosis was prevented by caspase-3 inhibitor. CONCLUSIONS. The data in this report show that FTY720 is a potential strong antitumor agent for cell line DU145, and provide the first evidence for in volvement of caspase-3 in apoptosis of an androgen-independent prostate can cer cell line. Activation of such caspases may provide a means for eliminat ing androgen-independent prostate cancer in humans. (C) 1999 Wiley-Liss, In c.