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Research Articles: Therapeutics

15-Deoxy-^12,14-prostaglandin J₂ induces death receptor 5 expression through mRNA stabilization independently of PPAR and potentiates TRAIL-induced apoptosis

¹ Department of Molecular-Targeting Cancer Prevention and ² Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science and ³ Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Requests for reprints: Toshiyuki Sakai, Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Phone: 81-75-251-5339; Fax: 81-75-241-0792. E-mail: tsakai{at}koto.kpu-m.ac.jp

15-Deoxy-^12,14-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 apoptosis-inducing 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 DR5-inducing effects of 15d-PGJ₂, and a potent PPAR inhibitor GW9662 failed to block DR5 induction by 15d-PGJ₂, suggesting PPAR-independent mechanisms. Cotreatment with 15d-PGJ₂ and TRAIL enhanced the sequential activation of caspase-8, caspase-10, caspase-9, 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 double-stranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ₂, significantly attenuated apoptosis induced by cotreatment with 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]

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Received 1/13/06; revised 5/12/06; accepted 5/16/06.