Liu Guangming, Ma Wei-Ya, Bode Ann M, Zhang Yiguo, Dong Zigang
Hormel Institute, University of Minnesota, Austin 55912, USA.
J Biol Chem. 2003 Jan 24;278(4):2124-30. doi: 10.1074/jbc.M202443200. Epub 2002 Nov 13.
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.
环氧化酶（COX）是催化花生四烯酸转化为前列腺素的限速酶，前列腺素参与多种生理和病理生理反应。COX-2是COX的两种同工型之一，最近发现它在许多细胞和组织类型的致癌过程中起重要作用。COX-2抑制剂属于非甾体抗炎药家族，由于其对COX-2的抑制作用，被认为在许多生物学活性如肿瘤化学预防中有效。然而，在本研究中我们发现，吡罗昔康（一种通用的COX抑制剂）和NS-398（一种COX-2选择性抑制剂）都能有效抑制紫外线B（UVB）或12-O-十四烷酰佛波醇-13-乙酸酯在小鼠表皮JB6细胞中诱导的转录因子激活蛋白1（AP-1）的激活。这些COX-2抑制剂也能抑制12-O-十四烷酰佛波醇-13-乙酸酯诱导的细胞转化。UVB显著增加了转染了AP-1荧光素酶报告基因的Cox-2（-/-）成纤维细胞中的AP-1活性，而这种增加被NS-389或吡罗昔康阻断。在JB6、Cox-2（-/-）或野生型Cox-2（+/ +）细胞中，NS-398和吡罗昔康都抑制了UVB诱导的c-Jun氨基末端激酶的磷酸化，c-Jun氨基末端激酶是激活AP-1/c-Jun复合物的激酶。基于我们的结果，我们提出COX-2抑制剂NS-398或吡罗昔康对AP-1活性的抑制可能通过一种独立于COX-2的机制发生。
