Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-κB

Kyung Soo Chun, Hyun Ho Cha, Jun Wan Shin, Hye Kyung Na, Kwang Kyun Park, Won Yoon Chung, Young Joon Surh

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112 Citations (Scopus)


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 to the dorsal skin of female ICR mice of 10 nmol TPA led to maximal induction of iNOS and COX-2 protein expression at ∼2 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 dose. 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 an anti-nitrotyrosine antibody reveals enhanced levels of nitrotyrosine protein localized in epidermal and dermal layers. Topical application of 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-κB activation in mouse skin, which was associated with the degradation of IκBα. Topical application of inhibitors of NF-κB, such as pyrrolidine dithiocarbamate or N-α-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 with SN50, a specific inhibitor of nuclear translocation of NF-κB. Mouse keratinocytes treated with SNP exhibited an elevated NF-κB-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 weeks. In conclusion, up-regulation of COX-2 by NO may be mediated by activation of NF-κB in mouse skin, which provides a molecular mechanism by which COX-2 is induced during tumor promotion.

Original languageEnglish
Pages (from-to)445-454
Number of pages10
Issue number3
Publication statusPublished - 2004 Mar

Bibliographical note

Funding Information:
This manuscript was prepared from a dissertation by K.-S.Chun in partial fulfillment of the requirement for a PhD degree at Seoul National University. This work was supported by a grant (R01-2000-000-00120-0) from the Basic Research Program of the Korea Science and Engineering Foundation (KOSEF).

All Science Journal Classification (ASJC) codes

  • Cancer Research


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