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CELLULAR AND MOLECULAR

Peroxisome Proliferator-Activated Receptor- Activator 15-Deoxy-^12,14-Prostaglandin J₂ Inhibits Neuroblastoma Cell Growth through Induction of Apoptosis: Association with Extracellular Signal-Regulated Kinase Signal Pathway

National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, Korea (E.J.K., K.S.P., S.Y.C.); College of Pharmacy, Ewha Woman's University, Seoul, Korea (Y.Y.S.); College of Pharmacy, Chungbuk National University, Chungbuk, Korea (D.C.M., Y.S.S., K.S.K., S.S., Y.P.Y., M.K.L., K.W.O., J.T.H.); and Laboratory of Cellular Biology, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea (D.Y.Y.)

Peroxisome proliferator-activated receptor- (PPAR-) ligands have been demonstrated to inhibit growth of several cancer cells. Here, we investigated whether one of the PPAR- ligands, 15-deoxy-^12,14-prostaglandin J2 (15-deoxy-PGJ₂) inhibits cell growth of two human neuroblastoma cells (SK-N-SH and SK-N-MC) in a PPAR--dependent manner. PPAR- was expressed in these cells, and 15-deoxy-PGJ₂ increased expression, DNA binding activity, and transcriptional activity of PPAR-. 15-Deoxy-PGJ₂ also inhibited cell growth in time- and dose-dependent manners in both cells. Cells were arrested in G₂/M phase after 15-deoxy-PGJ₂ treatment with concomitant increase in the expression of G₂/M phase regulatory protein cyclin B1 but decrease in the expression of cdk2, cdk4, cyclin A, cyclin D1, cyclin E, and cdc25C. Conversely, related to the growth inhibitory effect, 15-deoxy-PGJ₂ increased the induction of apoptosis in a dose-dependent manner. Consistent with the induction of apoptosis, 15-deoxy-PGJ₂ increased the expression of proapoptotic proteins caspase 3, caspase 9, and Bax but down-regulated antiapoptotic protein Bcl-2. 15-Deoxy-PGJ₂ also activated extracellular signal-regulated kinase (ERK) 2. In addition, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor PD98059 (2'-amino-3'-methoxyflavone) decreased 15-deoxy-PGJ₂-induced ERK2 activation, and expression of PPAR-, capase-3, and cyclin B1. Moreover, MEK1/2 inhibitor PD98059 significantly prevented against the 15-deoxy-PGJ₂-induced cell growth inhibition. We also found that PPAR- antagonist GW9662 (2-chloro-5-nitro-N-phenylbenzamide) reversed the 15-deoxy-PGJ₂-induced cell growth inhibition, PPAR- expression, and activation of ERK2. These results demonstrate that 15-deoxy-PGJ₂ inhibits growth of human neuroblastoma cells via the induction of apoptosis in a PPAR--dependent manner through activation of ERK pathway and suggest that 15-deoxy-PGJ₂ may have promising application as a therapeutic agent for neuroblastoma.

Address correspondence to: Dr. Jin Tae Hong, College of Pharmacy, Chungbuk National University, 48, Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea. E-mail: jinthong{at}cbucc.chungbuk.ac.kr

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