Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells

Takumi Shiraishi, Tatsushi Yoshida, Susumu Nakata, Mano Horinaka, Miki Wakada, Yoichi Mizutani, Tsuneharu Miki, Toshiyuki Sakai
2005 Cancer Research  
Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L). In this study, we showed that tunicamycin, a naturally occurring antibiotic, is a potent enhancer of TRAIL-induced apoptosis through upregulation of DR5 expression. Tunicamycin significantly sensitized PC-3, androgen-independent human prostate cancer cells, to TRAIL-induced apoptosis. The tunicamycinmediated enhancement of TRAIL-induced apoptosis
more » ... as markedly blocked by a recombinant human DR5/Fc chimeric protein. Tunicamycin and TRAIL cooperatively activated caspase-8, -10, -9, and -3 and Bid cleavage and this activation was also blocked in the presence of the DR5/Fc chimera. Tunicamycin up-regulated DR5 expression at the mRNA and protein levels in a dose-dependent manner. Furthermore, the tunicamycin-mediated sensitization to TRAIL was efficiently reduced by DR5 small interfering RNA, suggesting that the sensitization was mediated through induction of DR5 expression. Tunicamycin increased DR5 promoter activity and this enhanced activity was diminished by mutation of a CHOPbinding site. In addition, suppression of CHOP expression by small interfering RNA reduced the tunicamycin-mediated induction of DR5. Of note, tunicamycin-mediated induction of CHOP and DR5 protein expression was not observed in normal human peripheral blood mononuclear cells. Moreover, tunicamycin did not sensitize the cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may be a promising candidate for prostate cancer therapy. (Cancer Res 2005; 65(14): 6364-70) Requests for reprints: Toshiyuki Sakai,
doi:10.1158/0008-5472.can-05-0312 pmid:16024639 fatcat:arickws3l5hx7ot44qrsor5kqa