Journal Article

<i>cis-</i>9,<i>trans-</i>11-Conjugated linoleic acid down-regulates phorbol ester-induced NF-κB activation and subsequent COX-2 expression in hairless mouse skin by targeting IκB kinase and PI3K-Akt

Dal-Mi Hwang, Joydeb Kumar Kundu, Jun-Wan Shin, Jung-Chul Lee, Hyong Joo Lee and Young-Joon Surh

in Carcinogenesis

Volume 28, issue 2, pages 363-371
Published in print August 2006 | ISSN: 0143-3334
Published online February 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl151
cis-9,trans-11-Conjugated linoleic acid down-regulates phorbol ester-induced NF-κB activation and subsequent COX-2 expression in hairless mouse skin by targeting IκB kinase and PI3K-Akt

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Conjugated linoleic acid (CLA) has been reported to inhibit mouse skin carcinogenesis, particularly in the promotion stage, but underlying molecular mechanisms remain poorly understood. Since persistent induction of cyclooxygenase-2 (COX-2) is frequently implicated in carcinogenesis, we investigated the effect of cis-9,trans-11-CLA (9Z,11E-CLA) on the tumor promoter-induced COX-2 expression in HR-1 hairless mouse skin in vivo. Topical application of 9Z,11E-CLA caused significant inhibition of COX-2 expression at 6 h induced by 10 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) in HR-1 mouse skin. Since NF-κB is known to regulate COX-2 gene expression, we determined the effect of 9Z,11E-CLA on TPA-induced activation of this transcription factor. Treatment of mouse skin with 9Z,11E-CLA reduced TPA-induced DNA binding as well as nuclear translocation of NF-κB by blocking phosphorylation and subsequent degradation of IκBα. In addition, 9Z,11E-CLA attenuated TPA-induced phosphorylation of extracellular signal-regulated protein kinase, p38 mitogen-activated protein kinase and Akt. To further elucidate the molecular mechanism underlying the inactivation of NF-κB by 9Z,11E-CLA, we investigated its effect on TPA-induced activation of IκB kinase (IKK), an upstream kinase that regulates NF-κB via phosphorylation and degradation of IκBα. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKKα/β in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKβ-specific inhibitor SC-514 (1 μmol) attenuated TPA-induced activation of Akt and NF-κB, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-κB driven-COX-2 expression by blocking the IKK and PI3K-Akt signaling in TPA-treated hairless mouse skin in vivo, which may account for its previously reported anti-tumor promoting effects.

Journal Article.  5856 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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