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

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Blank15-Deoxy-{Delta}12,14-prostaglandin J2 induces death receptor 5 expression

through mRNA stabilization independently of PPAR{gamma} and potentiates

TRAIL-induced apoptosis.

S Nakata, T Yoshida, T Shiraishi, M Horinaka, J Kouhara, M Wakada, and T

Sakai

Mol. Cancer Ther., July 1, 2006; 5(7): 1827-35.

Department of Molecular-Targeting Cancer Prevention, Graduate School of

Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji,

Kamigyo-ku, Kyoto 602-8566, Japan. tsakai@....

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. [Mol Cancer Ther 2006;5(7):1827-35].

PMID: 16891469