NS-398 and piroxicam suppress UVB-induced activator protein 1 activity by mechanisms independent of cyclooxygenase-2

Guangming Liu, Wei-Ya Ma, Ann M Bode, Yiguo Zhang, Zigang Dong
Journal of Biological Chemistry 2003 January 24, 278 (4): 2124-30
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.

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