title: 15-Deoxy-Delta12,14-prostaglandin J(2) induces death receptor 5 expression through mRNA stabilization independently of PPARgamma and potentiates TRAIL-induced apoptosis.
abstract: 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), 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 gamma (PPARgamma). 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-PGJ(2) 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-PGJ(2) significantly increased DR5 mRNA stability, whereas it did not activate DR5 promoter activity. Synthetic PPARgamma agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ(2), and a potent PPARgamma inhibitor GW9662 failed to block DR5 induction by 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. Cotreatment with 15d-PGJ(2) 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-PGJ(2) and TRAIL. Moreover, a double-stranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ(2), significantly attenuated apoptosis induced by cotreatment with 15d-PGJ(2) and TRAIL. These results suggest that 15d-PGJ(2) is a potent sensitizer of TRAIL-mediated cancer therapeutics through DR5 up-regulation.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakata
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Takumi
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Mano
authors.initials: M
authors.lastname: Horinaka
authors.forename: Junji
authors.initials: J
authors.lastname: Kouhara
authors.forename: Miki
authors.initials: M
authors.lastname: Wakada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D000077154:Rosiglitazone; D053221:TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000077154:Rosiglitazone; D020169:Caspases; D015230:Prostaglandin D2; D000077205:Pioglitazone