cis-9,trans-11-Conjugated linoleic acid down-regulates phorbol ester-induced NF- B activation and subsequent COX-2 expression in hairless mouse skin by targeting I B kinase and PI3K-Akt
Copyright policy )cis-9,trans-11-Conjugated linoleic acid down-regulates phorbol ester-induced NF- B activation and subsequent COX-2 expression in hairless mouse skin by targeting I B kinase and PI3K-Akt
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-kappaB 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-kappaB by blocking phosphorylation and subsequent degradation of IkappaBalpha. 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-kappaB by 9Z,11E-CLA, we investigated its effect on TPA-induced activation of IkappaB kinase (IKK), an upstream kinase that regulates NF-kappaB via phosphorylation and degradation of IkappaBalpha. 9Z,11E-CLA treatment down-regulated phosphorylation and catalytic activities of IKKalpha/beta in TPA-treated mouse skin. Co-treatment of mouse skin with the IKKbeta-specific inhibitor SC-514 (1 micromol) attenuated TPA-induced activation of Akt and NF-kappaB, and also the expression of COX-2 in hairless mouse skin. Taken together, 9Z,11E-CLA inhibits NF-kappaB 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.
- Seoul National University of Science and Technology Korea (Republic of)
- Seoul National University Korea (Republic of)
Male, Mice, Hairless, Base Sequence, NF-kappa B, I-kappa B Kinase, Enzyme Activation, Mice, Phosphatidylinositol 3-Kinases, Cyclooxygenase 2, Animals, Tetradecanoylphorbol Acetate, Linoleic Acids, Conjugated, Phosphorylation, Proto-Oncogene Proteins c-akt, DNA Primers, Skin
Male, Mice, Hairless, Base Sequence, NF-kappa B, I-kappa B Kinase, Enzyme Activation, Mice, Phosphatidylinositol 3-Kinases, Cyclooxygenase 2, Animals, Tetradecanoylphorbol Acetate, Linoleic Acids, Conjugated, Phosphorylation, Proto-Oncogene Proteins c-akt, DNA Primers, Skin
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