Involvement of c-jun N-terminal kinase activation in 15-deoxy-delta12,14-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) J(2) metabolism, 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)), and PGA(1) 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 PPARalpha or PPARgamma, indicating the possibility that 15d-PGJ(2) and PGA(1) induced apoptosis through PPAR-independent pathway. Moreover, 15d-PGJ(2) and PGA(1) 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-PGJ(2) and PGA(1), 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-PGJ(2) and PGA(1). Overexpression of DN-JNK significantly repressed both endogenous JNK and caspase-3 activity, and subsequently decreased apoptosis induced by 15d-PGJ(2) and PGA(1). These results suggested that CyPGs, such as 15d-PGJ(2) and PGA(1), activated JNK signaling pathway, and that JNK activation may be involved in 15d-PGJ(2)- and PGA(1)-induced apoptosis.
Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
Jean-Dean
JD
Liu
Shyr-Yi
SY
Lin
Yuan-Soon
YS
Ho
Shiann
S
Pan
Ling-Fang
LF
Hung
Shu-Huei
SH
Tsai
Jen-Kun
JK
Lin
Yu-Chih
YC
Liang
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D011454:Prostaglandins A / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D011454:Prostaglandins A; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015230:Prostaglandin D2; C100573:prostaglandin A1