Carcinogenesis Advance Access published online on November 21, 2003
Carcinogenesis, doi:10.1093/carcin/bgh021
© 2003 by Oxford University Press
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CARCINOGENESIS
1 College of Pharmacy, Seoul National University, Seoul, 151-742, Korea
* Corresponding author. E-mail: surh{at}plaza.snu.ac.kr.
Received 9 July 2003
; revised 2 November 2003
; accepted 4 November 2003
Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are frequently overexpressed in tumor tissues or transformed cells. In the present work, we assessed the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on expression of iNOS and COX-2 in mouse skin. Topical application of the dorsal skin of female ICR mice with 10 nmol TPA led to maximal induction of iNOS and COX-2 protein expression at about 2 h and 4 h, respectively. When applied topically onto shaven backs of mice 30 min prior to TPA, the NOS inhibitor aminoguanidine (AG) inhibited the expression of COX-2 protein at the pharmacologically effective doses. Pretreatment with a more specific iNOS inhibitor NG-nitro-L-arginine-methyl ester also suppressed TPA-induced COX-2 expression. Immunohistochemical analysis of TPA-treated mouse skin using nitrotyrosine antibody revealed enhanced levels of nitrotyrosine protein localized in epidermal and dermal layers. Topical application of nitric oxide (NO) donors, such as sodium nitroprusside (SNP) and S-nitroso-N-acetyl-D,L-penicillamine, induced expression of COX-2 in mouse skin, which was attenuated by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide. SNP treatment stimulated NF-
Nitric oxide, Inducible nitric oxide synthase, Cyclooxygenase, NF-Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-
B
2 College of Dentistry, Yonsei University, Seoul, 120-749, Korea
B activation in mouse skin, which was associated with the degradation of IB
. Topical application of inhibitors of NF-B, such as pyrrolidine dithiocarbamate or N--p-tosyl-L-lysine chloromethylketone, inhibited the SNP-induced COX-2 expression. SNP induced a weak but concentration-related increase in COX-2 expression in cultured mouse keratinocytes, which was abolished by treatment of SN50, a specific inhibitor of nuclear translocation of NF-B. Mouse keratinocytes treated with SNP exhibited an elevated NF-B-driven COX-2 promoter activity. Topical application of AG (10 µmol) prior to each TPA treatment after initiation reduced the multiplicity of papillomas by 44% at 22 week. Taken together, up-regulation of COX-2 by NO may be mediated by activation of NF-B in mouse skin, which provides a molecular mechanism by which COX-2 is induced during tumor promotion.B, Mouse skin carcinogenesis
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