Involvement of c-jun N-terminal kinase activation in 15-deoxy-Δ^12,14-prostaglandin J₂- and prostaglandin A₁-induced apoptosis in AGS gastric epithelial cells

Cyclopentenone prostaglandins (CyPGs), derivatives of arachidonic acid, have been suggested to exert growth inhibitory activity through peroxisome proliferator-activated receptor (PPAR)-dependent and -independent mechanisms. Here we examined various eicosanoids for growth inhibition and found that the terminal derivative of prostaglandin (PG) J₂ metabolism, 15-deoxy-Δ^12,14-pGJ₂ (15d-PGJ₂), and PGA₁ markedly inhibited the growth and induced apoptosis in AGS gastric carcinoma cells. There were no significant increases in cell death and DNA fragmentation in the cells with overexpression of PPARα or PPARγ, indicating the possibility that 15d-PGJ₂ and PGA₁ induced apoptosis through PPAR-independent pathway. Moreover, 15d-PGJ₂ and PGA₁ activated the c-jun N-terminal kinase (JNK) and caspase-3 activity in dose- and time-dependent manners. To examine further the role of JNK signaling cascades in apoptosis induced by 15d-PGJ₂ and PGA₁, we transfected dominant-negative (DN) mutants of JNK plasmid into the cells to analyze the apoptotic characteristics of cells overexpressing DN-JNK following exposure to 15d-PGJ₂ and PGA₁. Overexpression of DN-JNK significantly repressed both endogenous JNK and caspase-3 activity, and subsequently decreased apoptosis induced by 15d-PGJ₂ and PGA₁. These results suggested that CyPGs, such as 15d-PGJ₂ and PGA₁, activated JNK signaling pathway, and that JNK activation may be involved in 15d-PGJ₂- and PGA₁-induced apoptosis.