Nitric oxide induces apoptosis via AP-1-driven upregulation of COX-2 in rat pheochromocytoma cells.
Cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis, is induced in many cells by numerous inflammatory mediators, including nitric oxide (NO). Upregulation of COX-2 expression has been implicated in the pathophysiology of neuronal cell death. In the present study, we have found that the NO-induced upregulation of COX-2 via activation of activator protein-1 (AP-1) signaling leads to apoptotic cell death. Cultured rat pheochromocytoma (PC12) cells treated with sodium nitroprusside (SNP), a NO-releasing compound, exhibited marked induction of COX-2 expression, which was associated with apoptotic cell death as evidenced by internucleosomal DNA fragmentation, cleavage of poly(ADP-ribose) polymerase, activation of caspase-3, accumulation of p53, increased Bax/Bcl-XL ratio, and dissipation of mitochondrial membrane potential. In addition to the upregulation of COX-2 expression, SNP treatment led to activation of AP-1. Pretreatment of PC12 cells with c-fos antisense oligonucleotide abolished the NO-induced increase in DNA binding of AP-1 and upregulation of COX-2 expression. Furthermore, pretreatment with a selective COX-2 inhibitor (SC58635) rescued the PC12 cells from the apoptotic cell death induced by NO. Similar results were obtained when the NO-induced upregulation of COX-2 expression was blocked by the siRNA interference. These results suggest that excessive NO production during inflammation induces apoptosis in PC12 cells through AP-1-mediated upregulation of COX-2 expression.
Li
Mei-Hua
MH
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea.
Jang
Jung-Hee
JH
Surh
Young-Joon
YJ
D000818:Animals; D017209:Apoptosis; D000068579:Celecoxib; D015971:Gene Expression Regulation, Enzymologic; D016762:Genes, fos / Q000235:genetics; D008954:Models, Biological; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D016716:PC12 Cells; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D015854:Up-Regulation
D020319:Oligodeoxyribonucleotides, Antisense; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D018808:Transcription Factor AP-1; D009599:Nitroprusside; D009569:Nitric Oxide; D000068579:Celecoxib