Involvement of c‐jun N‐terminal kinase activation in 15‐deoxy‐δ12,14‐prostaglandin J2–and prostaglandin A1–induced apoptosis in AGS gastric epithelial cells

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Abstract
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‐Δ12,14‐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.