TY - JOUR
T1 - 15-Deoxy-Δ12,14-prostaglandin J2 induces death receptor 5 expression through mRNA stabilization independently of PPARγ and potentiates TRAIL-induced apoptosis
AU - Nakata, Susumu
AU - Yoshida, Tatsushi
AU - Shiraishi, Takumi
AU - Horinaka, Mano
AU - Kouhara, Junji
AU - Wakada, Miki
AU - Sakai, Toshiyuki
PY - 2006/7
Y1 - 2006/7
N2 - 15-Deoxy-Δ12,14-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 γ (PPARγ). 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 neo-plastic 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 PPARγ agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ2, and a potent PPARγ inhibitor GW9662 failed to block DR5 induction by 15d-PGJ2, suggesting PPARγ-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.
AB - 15-Deoxy-Δ12,14-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 γ (PPARγ). 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 neo-plastic 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 PPARγ agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ2, and a potent PPARγ inhibitor GW9662 failed to block DR5 induction by 15d-PGJ2, suggesting PPARγ-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.
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UR - http://www.scopus.com/inward/citedby.url?scp=33748323449&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-06-0023
DO - 10.1158/1535-7163.MCT-06-0023
M3 - Article
C2 - 16891469
AN - SCOPUS:33748323449
SN - 1535-7163
VL - 5
SP - 1827
EP - 1835
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 7
ER -