Journal Article

Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-κB activation

Kyung-Soo Chun, Young-Sam Keum, Seong Su Han, Yong-Sang Song, Su-Hyeong Kim and Young-Joon Surh

in Carcinogenesis

Volume 24, issue 9, pages 1515-1524
Published in print September 2003 | ISSN: 0143-3334
Published online September 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg107
Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-κB activation

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Recently, there have been considerable efforts to search for naturally occurring substances for the intervention of carcinogenesis. Many components derived from dietary or medicinal plants have been found to possess substantial chemopreventive properties. Curcumin, a yellow coloring ingredient of turmeric (Curcuma longa L., Zingiberaceae), has been shown to inhibit experimental carcinogenesis and mutagenesis, but molecular mechanisms underlying its chemopreventive activities remain unclear. In the present work, we assessed the effects of curcumin on 12-O- tetradecanoylphorbol-13-acetate (TPA)-induced expression of cyclooxygenase-2 (COX-2) in female ICR mouse skin. Topical application of the dorsal skin of female ICR mice with 10 nmol TPA led to maximal induction of cox-2 mRNA and protein expression at ∼1 and 4 h, respectively. When applied topically onto shaven backs of mice 30 min prior to TPA, curcumin inhibited the expression of COX-2 protein in a dose-related manner. Immunohistochemical analysis of TPA-treated mouse skin revealed enhanced expression of COX-2 localized primarily in epidermal layer, which was markedly suppressed by curcumin pre-treatment. Curcumin treatment attenuated TPA- stimulated NF-κB activation in mouse skin, which was associated with its blockade of degradation of the inhibitory protein IκBα and also of subsequent translocation of the p65 subunit to nucleus. TPA treatment resulted in rapid activation via phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein (MAP) kinases, which are upstream of NF-κB. The MEK1/2 inhibitor U0126 strongly inhibited NF-κB activation, while p38 inhibitor SB203580 failed to block TPA-induced NF-κB activation in mouse skin. Furthermore, U0126 blocked the IκBα phosphorylation by TPA, thereby blocking the nuclear translocation of NF-κB. Curcumin inhibited the catalytic activity of ERK1/2 in mouse skin. Taken together, suppression of COX-2 expression by inhibiting ERK activity and NF-κB activation may represent molecular mechanisms underlying previously reported antitumor promoting effects of this phytochemical in mouse skin tumorigenesis.

Keywords: AP-1, activator protin 1; COX, cyclooxygenase; DTT, dithiothreitol; EMSA, electrophoretic mobility shift assay; ERK, extra-cellular signal-regulated kinase; MAP kinase, mitogen-activated protein kinase; MEK, MAP kinase kinase; PG, prostaglandin; SDS, sodium dodecyl sulfate; TPA, 12-O-tetradecanoylphorbol-13-acetate

Journal Article.  6969 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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