종양 촉진제로 유도된 Cyclooxygenase-2와 Inducible Nitric Oxide Synthesis 발현 조절에 있어서의 NF-kB의 역할
Co-regulation of Phorbol Ester-Induced Expression of Cyclooxygenease-2 (COX-2) and inducible Nitric Oxide Synthase (iNOS): Possible Involvement of NF-kB
천경수, 한성수, 김정환, 서영준,
소속 상세정보
천경수 ( Chun Kyung-Soo )
서울대학교 약학대학
한성수 ( Han Seong-Su )
서울대학교 약학대학
김정환 ( Kim Jung-Hwan )
서울대학교 약학대학
서영준 ( Surh Young-Joon )
서울대학교 약학대학
KMID : 0603519990040030166
Abstract
There has been accumulating evidence supporting that both cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) play pivotal role in inflammatory processes. COX-2 and iNOS catalyse the production of PGE2 and nitric oxide (NO) respectively that are important proinflammatory mediators. Since inflammation is closely related to multi-stage carcinogenesis, particularly to tumor promotion, substances with substantial anti-inflammatory properties may exert potential chemopreventive activities. In the present work, we found that typical application of the dorsal skin of female ICR mice with the tumor promoter 12-O-tetradecanoylphorbol-13acetate (TPA) led to significant elevation of both COX-2 and iNOS in time- and dose-related manners. Pretreatment of mice with aminoguanidine, a selective inhibitor of iNOS, significantly suppressed the TPA-induced increases in COX-2 protein levels, indicating that the expression of both COX-2 and iNOS is coregulated. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor kappa B (NF-KB) is involved in regulation of COX-2 and iNOS expression. TPA treatment caused marked activation of epidermal NF-KB as assessed by electrophoretic mobility shift assay (EMSA), compared with that observed in the acetone-treated control animals. NF-KB activation proceeded the increased expression of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS activities via down regulation of NF-KB activation. In another study, we found that yakuchinone A and yakuchinone B, pungent diarylheptanoids isolated from Alpinia oxyphylla Miqyel (Zingiberaceae), markedly inhibited TPA-stimulated NF-KB DNA binding as well as expression of COX-2 and iNOS when applied topically onto shaven backs of mice 30 min prior to the tumor promoter (10 nmol). Likewise, both yakuchinone A and yakuchinone B suppressed COX-2 protein expression induced by TPA in the immortalized human mammary cell line (MCF-10A). The effect of the NF-KB inactivator pyrrolidine dithiocarbamate on tumor promoter-induced COX-2 and iNOS expression is under investigation in our laboratory.
키워드
Cycoolxygenase-2(COX-2); induced Nitric oxide synthase(iNOS); Nuclear factor
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