15-Deoxy-#-prostaglandin J2 induces death receptor 5 expression through mRNA stabilization independently of PPAR; and potentiates TRAIL-induced apoptosis

15-Deoxy-#-prostaglandin J2 (15d-PGJ2), the terminal derivative of the PGJ series, is emerging as a potent antineoplastic agent among cyclopentenone prostaglandins derivatives and also known as the endogenous ligand of peroxisome proliferator-activated receptor ; (PPAR;). On the other hand, death receptor 5 (DR5) is a specific receptor for tumor necrosis factor–related apoptosisinducing ligand (TRAIL), which is one of the most promising candidates for new cancer therapeutics. Here, we report that 15d-PGJ2 induces DR5 expression at both mRNA and protein levels, resulting in the synergistic sensitization of TRAIL-induced apoptosis in human neoplastic cells, such as Jurkat human leukemia cells or PC3 human prostate cancer cells. 15d-PGJ2 significantly increased DR5 mRNA stability, whereas it did not activate DR5 promoter activity. Synthetic PPAR; agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5inducing effects of 15d-PGJ2, and a potent PPAR; inhibitor GW9662 failed to block DR5 induction by 15dPGJ2, suggesting PPAR;-independent mechanisms. Cotreatment with 15d-PGJ2 and TRAIL enhanced the sequential activation of caspase-8, caspase-10, caspase9, caspase-3, and Bid. DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 inhibitor efficiently blocked the activation of these apoptotic signal mediators and the induction of apoptotic cell death enhanced by cotreatment with 15d-PGJ2 and TRAIL. Moreover, a doublestranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ2, significantly attenuated apoptosis induced by cotreatmentwith 15d-PGJ2 and TRAIL. These results suggest that 15d-PGJ2 is a potent sensitizer of TRAIL-mediated cancer therapeutics through DR5 up-regulation. [Mol Cancer Ther 2006;5(7):1827–35]