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: Jung-Hwan Kim, Ki Won Lee, Min-Won Lee, Hyong Joo Lee, Sung-Hoon Kim, Young-Joon Surh
• Journal: FEBS letters (FEBS Lett) Vol. 580 Issue 2 Pg. 385-92 (Jan 23 2006) ISSN: 0014-5793 [Print] England
• PMID: 16380122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Catechols
• Diarylheptanoids
• Membrane Proteins
• NF-kappa B
• hirsutenone
• Cyclooxygenase 2
• PTGS2 protein, human
• Matrix Metalloproteinase 9
• Dinoprostone
• Tetradecanoylphorbol Acetate

Topics

• Active Transport, Cell Nucleus (physiology)
• Catechols (pharmacology)
• Cell Line
• Cell Movement (physiology)
• Cyclooxygenase 2 (metabolism)
• Diarylheptanoids (pharmacology)
• Dinoprostone (biosynthesis)
• Epithelial Cells (cytology, metabolism)
• Gene Expression Regulation, Enzymologic
• Genes, Reporter
• Humans
• Mammary Glands, Human (cytology)
• Matrix Metalloproteinase 9 (metabolism)
• Membrane Proteins (metabolism)
• Molecular Structure
• NF-kappa B (metabolism)
• Tetradecanoylphorbol Acetate (metabolism)
• Transcription, Genetic
• Up-Regulation