Carcinogenesis Advance Access published online on March 19, 2007
Carcinogenesis, doi:10.1093/carcin/bgm054
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Humulone inhibits phorbol ester-induced COX-2 expression in mouse skin by blocking activation of NF-
B and AP-1: IB kinase and c-Jun-N-terminal kinase as respective potential upstream targets
1 National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742
1,2 Cancer Research Institute, Seoul National University, Seoul 110-799, South Korea
* To whom correspondence should be addressed: Professor Young-Joon Surh, College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-ku, Seoul 151-742, Korea. Fax) +82 2 874-9775; Phone) +82 2 880-7845; E-mail) surh{at}plaza.snu.ac.kr
Humulone, a bitter acid derived from hop (Humulus lupulus L.), possesses antioxidative, anti-inflammatory and other biologically active activities. Although humulone has been reported to inhibit chemically induced mouse skin tumor promotion, the underlying mechanisms are yet to be elucidated. Since an inappropriate overexpression of cyclooxygenase-2 (COX-2) is implicated in carcinogenesis, we investigated effects of humulone on COX-2 expression in mouse skin stimulated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of humulone (10 µmol) significantly inhibited TPA-induced epidermal COX-2 expression. Humulone also diminished TPA-induced DNA binding of nuclear factor-
B (NF-B) and activator protein-1 (AP-1). Pretreatment with humulone attenuated TPA-induced phosphorylation of p65, and nuclear translocation of NF-B subunit proteins. Humulone blunted TPA-induced activation IB kinase (IKK) in mouse skin, which accounts for its suppression of phosphorylation and subsequent degradation of IB
. An in vitro kinase assay revealed that humulone could directly inhibit the catalytic activity of IKKß. Humulone suppressed the activation of mitogen-activated protein (MAP) kinases in TPA-treated mouse skin. The roles of extracellular signal-regulated protein kinase-1/2 and p38 MAP kinase in TPA-induced activation of NF-B in mouse skin had been defined in our previous studies. The present study revealed that topical application of SP600125, a pharmacological inhibitor of c-Jun-N-terminal kinase, abrogated the activation of AP-1 and the expression of COX-2 in TPA-treated mouse skin. Taken together, humulone suppressed TPA-induced activation of NF-B and AP-1, and subsequent expression of COX-2 by blocking upstream kinases IKK and c-Jun-N-terminal kinase, respectively which may account for its antitumor promoting effects on mouse skin carcinogenesis.
Key Words: Humulone • Cyclooxygenase-2 • Mouse skin carcinogenesis • NF-B • AP-1
Received August 16, 2006; revised February 16, 2007; accepted March 1, 2007.
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