title: Hirsutenone inhibits phorbol ester-induced upregulation of COX-2 and MMP-9 in cultured human mammary epithelial cells: NF-kappaB as a potential molecular target.
abstract: 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 microM 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-kappaB) and translocation of p65, the functionally active NF-kappaB subunit, to the nucleus. The luciferase reporter gene assay revealed that hirsutenone abrogated the transcriptional activity of NF-kappaB. Treatment of MCF10A cells with N-alpha-Tosyl-l-phenylalanine chloromethyl ketone, a specific inhibitor of NF-kappaB, 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-kappaB, which may contribute to its chemopreventive effects.
authors.affiliation: College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Min-Won
authors.initials: MW
authors.lastname: Lee
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D002396:Catechols / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D036381:Diarylheptanoids / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D002396:Catechols; D036381:Diarylheptanoids; D008565:Membrane Proteins; D016328:NF-kappa B; C508777:hirsutenone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate