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, WonYoon Chung, Young Joon Surh

Research output: Contribution to journalReview article

100 Citations (Scopus)

Abstract

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
JournalCarcinogenesis
Volume25
Issue number3
DOIs
Publication statusPublished - 2004 Mar 1

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Cyclooxygenase 2
Nitric Oxide
Tetradecanoylphorbol Acetate
Skin
Nitroprusside
Nitric Oxide Synthase Type II
Keratinocytes
Imidazolines
Mouse Ptgs2 protein
Inbred ICR Mouse
Proteins
Penicillamine
NG-Nitroarginine Methyl Ester
Papilloma
Oxides
Lysine
Anti-Idiotypic Antibodies
Neoplasms
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Chun, K. S., Cha, H. H., Shin, J. W., Na, H. K., Park, K. K., Chung, W., & Surh, Y. J. (2004). Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-κB. Carcinogenesis, 25(3), 445-454. https://doi.org/10.1093/carcin/bgh021
Chun, Kyung Soo ; Cha, Hyun Ho ; Shin, Jun Wan ; Na, Hye Kyung ; Park, Kwang Kyun ; Chung, WonYoon ; Surh, Young Joon. / Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-κB. In: Carcinogenesis. 2004 ; Vol. 25, No. 3. pp. 445-454.
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Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-κB. / Chun, Kyung Soo; Cha, Hyun Ho; Shin, Jun Wan; Na, Hye Kyung; Park, Kwang Kyun; Chung, WonYoon; Surh, Young Joon.

In: Carcinogenesis, Vol. 25, No. 3, 01.03.2004, p. 445-454.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Nitric oxide induces expression of cyclooxygenase-2 in mouse skin through activation of NF-κB

AU - Chun, Kyung Soo

AU - Cha, Hyun Ho

AU - Shin, Jun Wan

AU - Na, Hye Kyung

AU - Park, Kwang Kyun

AU - Chung, WonYoon

AU - Surh, Young Joon

PY - 2004/3/1

Y1 - 2004/3/1

N2 - 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.

AB - 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.

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U2 - 10.1093/carcin/bgh021

DO - 10.1093/carcin/bgh021

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