Premium
Hirsutenone inhibits phorbol ester‐induced upregulation of COX‐2 and MMP‐9 in cultured human mammary epithelial cells: NF‐κB as a potential molecular target
Author(s) -
Kim Jung-Hwan,
Lee Ki Won,
Lee Min-Won,
Lee Hyong Joo,
Kim Sung-Hoon,
Surh Young-Joon
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2005.12.015
Subject(s) - downregulation and upregulation , nf κb , microbiology and biotechnology , chemistry , matrix metalloproteinase , tetradecanoylphorbol acetate , iκbα , cancer research , biology , signal transduction , biochemistry , protein kinase c , gene
Inappropriate upregulation of cyclooxygenase‐2 (COX‐2) and matrix metalloproteinases (MMPs) has been implicated in the pathogenesis of various types of cancer. In the present study, we investigated the effects of hirsutenone, a diarylheptanoid isolated from the medicinal plant Alnus hirsuta var. sibirica, on the expression of COX‐2 and MMP‐9 induced by the tumor promoter 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA) in MCF10A human breast epithelial cells. Treatment of MCF10A cells with TPA led to the expression of COX‐2 and MMP‐9. Hirsutenone at 12 μM inhibited the TPA‐induced COX‐2 expression at both the transcriptional and posttranscriptional levels. Hirsutenone also suppressed the synthesis of prostaglandin E 2 , one of the major products of COX‐2, and its catalytic activity. The upregulation of MMP‐9 by TPA was also significantly reduced by hirsutenone. Likewise, hirsutenone attenuated the invasiveness and motility of MCF10A cells stimulated with TPA. Hirsutenone blocked the TPA‐induced DNA binding of nuclear factor kappa B (NF‐κB) and translocation of p65, the functionally active NF‐κB subunit, to the nucleus. The luciferase reporter gene assay revealed that hirsutenone abrogated the transcriptional activity of NF‐κB. Treatment of MCF10A cells with N ‐alpha‐Tosyl‐ l ‐phenylalanine chloromethyl ketone, a specific inhibitor of NF‐κB, reduced the TPA‐induced expression of COX‐2 and MMP‐9. In summary, hirsutenone inhibits the TPA‐induced upregulation of COX‐2 and MMP‐9 in human breast epithelial cells, possibly by targeting NF‐κB, which may contribute to its chemopreventive effects.