Carcinogenesis Advance Access originally published online on March 19, 2007
Carcinogenesis 2007 28(7):1491-1498; 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, Shillim-dong, Kwanak-ku, Seoul 151-742, South Korea
2 Cancer Research Institute, Seoul National University, Seoul 110-799, South Korea
* To whom correspondence should be addressed. Tel: +82 2 880 7845; Fax: +82 2 874 9775; Email: 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 over-expression 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). Pre-treatment with humulone attenuated TPA-induced phosphorylation of p65 and nuclear translocation of NF-B subunit proteins. Humulone blunted TPA-induced activation of inhibitory kappaB (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 kinases (MAPKs) in TPA-treated mouse skin. The roles of extracellular signal-regulated protein kinase-1/2 and p38 MAPK 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 (JNK), 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 JNK, respectively, which may account for its antitumor-promoting effects on mouse skin carcinogenesis.
Abbreviations: AP-1, activator protein-1; COX-2, cyclooxygenase-2; DTT, dithiothreitol; EDTA, ethylenediaminetetraacetic acid; ERK, extracellular signal-regulated protein kinase; IB, inhibitory kappaB; IKK, IB kinase; JNK, c-Jun-N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-B, nuclear factor-kappaB; RT, room temperature; SDS, sodium dodecyl sulfate; TPA, 12-O-tetradecanoylphorbol-13-acetate
Received August 16, 2006; revised February 16, 2007; accepted March 1, 2007.
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