Peroxisome proliferator-activated receptor-gamma activator 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibits neuroblastoma cell growth through induction of apoptosis: Association with extracellular signal-regulated kinase signal pathway

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands have been demonstrated to inhibit growth of several cancer cells. Here, we investigated whether one of the PPAR-gamma ligands, 15-deoxy-Delta(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-gamma-dependent manner. PPAR-gamma was expressed in these cells, and 15-deoxy-PGJ(2) increased expression, DNA binding activity, and transcriptional activity of PPAR-gamma. 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'-methoxy-flavone) decreased 15-deoxy-PGJ(2)-induced ERK2 activation, and expression of PPAR-gamma, 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-gamma antagonist GW9662 (2-chloro-5-nitro-N-phenylbenzamide) reversed the 15-deoxy-PGJ(2)-induced cell growth inhibition, PPAR-gamma 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-gamma-dependent manner through activation of ERK pathway and suggest that 15-deoxy-PGJ(2) may have promising application as a therapeutic agent for neuroblastoma.