Abstract
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.
Highlights
COX inhibitors are known to function through the inhibition of the COX enzymes
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
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
Summary
COX inhibitors are known to function through the inhibition of the COX enzymes. Other potential mechanisms are still being considered [12]. COX inhibitors were reported to protect neurons against hypoxia/reperfusion through mechanisms independent of COX [13]. We and others have shown that nonsteroidal anti-inflammatory drugs can block mitogeninduced transcription activator protein 1 (AP-1) activity and transactivation [14]. Considering the important role of AP-1 in tumoroigensis, the inhibition of AP-1 is likely to be one of the major mechanisms involved in nonsteroidal anti-inflammatory drugs chemopreventive effects. The aim of this study was to determine whether a COX-2 highly selective inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398), or a general inhibitor of COX-2, 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamid-1,1-dioxid (piroxicam), is effective in blocking AP-1 activation and whether COX-2 is involved in the inhibitory effects
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