NS-398 and piroxicam suppress UVB-induced activator protein 1 activity by mechanisms independent of cyclooxygenase-2.
Cyclooxygenases (COX) are rate-limiting enzymes that catalyze the conversion of arachidonic acid to prostaglandins, which are involved in many physiological and pathophysiological responses. COX-2, one of two isoforms of COX, was recently found to play an important role in carcinogenesis in many cell and tissue types. COX-2 inhibitors, which belong to the family of nonsteroidal anti-inflammatory drugs, are believed to be effective in many biological activities such as tumor chemoprevention because of their inhibition of COX-2. However, in the present study we found that both piroxicam, a general COX inhibitor, and NS-398, a COX-2 selective inhibitor, effectively suppressed the activation of transcription factor activator protein 1 (AP-1) induced by ultraviolet B (UVB) or 12-O-tetradecanoylphorbol-13-acetate in mouse epidermal JB6 cells. These COX-2 inhibitors could also inhibit 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation. UVB significantly increased AP-1 activity in Cox-2(-/-) fibroblasts transfected with an AP-1 luciferase reporter gene, and this increase was blocked by NS-389 or piroxicam. In JB6, Cox-2(-/-), or wild-type Cox-2(+/+) cells, both NS-398 and piroxicam inhibited UVB-induced phosphorylation of c-Jun NH(2)-terminal kinases, the kinases that activate the AP-1/c-Jun complex. Based on our results, we propose that the inhibition of AP-1 activity by COX-2 inhibitors NS-398 or piroxicam may occur by a mechanism that is independent of COX-2.
Liu
Guangming
G
Hormel Institute, University of Minnesota, Austin 55912, USA.
Ma
Wei-Ya
WY
Bode
Ann M
AM
Zhang
Yiguo
Y
Dong
Zigang
Z
D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D010766:Phosphorylation; D010894:Piroxicam / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014466:Ultraviolet Rays
D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010894:Piroxicam; D004247:DNA; D008156:Luciferases; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate