Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosisin androgen-independent prostate cancer cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been re ported to induce cell death in a variety of transformed cells but spared th e normal cells. In this study, we examined its potential against advanced p rostate cancer cells. Treatment of PC-3 and DU145 cells with TRAIL caused a rapid apoptotic cell death, whereas tumor necrosis factor-alpha (TNF-alpha ) is ineffective unless in the presence of the protein synthesis inhibitor cycloheximide. The induction of apoptosis by TRAIL in PC-3 cells was mediat ed by a death receptor, DR 4, and the downstream caspases. Treatment of PC- 3 cells with TRAIL also activated c-Jun NH,terminal kinase 1 (JNK1); howeve r, inhibition of JNK1 activation by its dominant-negative mutant had little effect on TRAIL-induced apoptosis. Furthermore, TRAIL weakly stimulated nu clear factor kappa B activity in PC-3 cells. Interestingly, activation of n uclear factor kappa B pathway by pretreatment with TNF-alpha did not preven t the induction of apoptosis by TRAIL. These data indicate that TRAIL trigg ers apoptosis in advanced prostate cancer cells through the activation of c aspase cascades, which appears to be independent of TNF-alpha- and JNK-medi ated mechanisms.