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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 

E J KimK S ParkS Y ChungY Y SheenD C MoonY S SongK S KimS G SongY P YunM K LeeK W OhDo Young YoonJ T Hong

Publisher 

American Society for Pharmacology and Experimental Therapeutics (ASPET)

Issue Date 

2003

Citation 

Journal of Pharmacology and Experimental Therapeutics, vol. 307, no. 2, pp. 505-517

Keywords 

15 deoxy delta12,14 prostaglandin J2cell cycle proteincyclin dependent kinase 2cyclin dependent kinase 4mitogen activated protein kinasemitogen activated protein kinase inhibitorperoxisome proliferator activated receptor agonistperoxisome proliferator activated receptor antagonistperoxisome proliferator activated receptor gammaapoptosiscancer growth

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-PGJ2) 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-PGJ2 increased expression, DNA binding activity, and transcriptional activity of PPAR-γ. 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-γ, 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-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-PGJ2 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-PGJ2 may have promising application as a therapeutic agent for neuroblastoma.

ISSN 

0022-3565

Link 

http://dx.doi.org/10.1124/jpet.103.053876

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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