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Peroxisome Proliferator-Activated Receptor-γ Activator 15-Deoxy-Δ 12,14-Prostaglandin J 2 Inhibits Neuroblastoma Cell Growth through Induction of Apoptosis: Association with Extracellular Signal-Regulated Kinase Signal Pathway

Title
Peroxisome Proliferator-Activated Receptor-γ Activator 15-Deoxy-Δ 12,14-Prostaglandin J 2 Inhibits Neuroblastoma Cell Growth through Induction of Apoptosis: Association with Extracellular Signal-Regulated Kinase Signal Pathway
Authors
Kim E.J.Park K.S.Chung S.Y.Sheen Y.Y.Moon D.C.Song Y.S.Kim K.S.Song S.Yun Y.P.Lee M.K.Oh K.W.Yoon D.Y.Hong J.T.
Ewha Authors
신윤용
SCOPUS Author ID
신윤용scopus
Issue Date
2003
Journal Title
Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565JCR Link
Citation
vol. 307, no. 2, pp. 505 - 517
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands have been demonstrated to inhibit growth of several cancer cells. Here, we investigated whether one of the PPAR-γ ligands, 15-deoxy-Δ 12,14-prostaglandin J2 (15-deoxy-PGJ 2) inhibits cell growth of two human neuroblastoma cells (SK-N-SH and SK-N-MC) in a PPAR-γ-dependent manner. PPAR-γ was expressed in these cells, and 15-deoxy-PGJ 2 increased expression, DNA binding activity, and transcriptional activity of PPAR-γ. 15-Deoxy-PGJ 2 also inhibited cell growth in time- and dose-dependent manners in both cells. Cells were arrested in G 2/M phase after 15-deoxy-PGJ 2 treatment with concomitant increase in the expression of G 2/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-PGJ 2 increased the induction of apoptosis in a dose-dependent manner. Consistent with the induction of apoptosis, 15-deoxy-PGJ 2 increased the expression of proapoptotic proteins caspase 3, caspase 9, and Bax but down-regulated antiapoptotic protein Bcl-2. 15-Deoxy-PGJ 2 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-PGJ 2-induced ERK2 activation, and expression of PPAR-γ, capase-3, and cyclin B1. Moreover, MEK1/2 inhibitor PD98059 significantly prevented against the 15-deoxy-PGJ 2-induced cell growth inhibition. We also found that PPAR-γ antagonist GW9662 (2-chloro-5-nitro-N-phenylbenzamide) reversed the 15-deoxy-PGJ 2-induced cell growth inhibition, PPAR-γ expression, and activation of ERK2. These results demonstrate that 15-deoxy-PGJ 2 inhibits growth of human neuroblastoma cells via the induction of apoptosis in a PPAR-γ-dependent manner through activation of ERK pathway and suggest that 15-deoxy-PGJ 2 may have promising application as a therapeutic agent for neuroblastoma.
DOI
10.1124/jpet.103.053876
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약학대학 > 약학과 > Journal papers
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