title: Ascochlorin inhibits matrix metalloproteinase-9 expression by suppressing activator protein-1-mediated gene expression through the ERK1/2 signaling pathway: inhibitory effects of ascochlorin on the invasion of renal carcinoma cells.
abstract: The expression of matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. Here we examined the effect of ascochlorin, a prenyl-phenol anti-tumor compound from the fungus Ascochyta viciae, on the regulation of signaling pathways that control MMP-9 expression in human renal carcinoma (Caki-1) cells. Ascochlorin reduced the invasive activity of Caki-1 cells and inhibited phorbol 12-myristate 13-acetate-induced increases in MMP-9 expression and activity in a dose-dependent manner. Reporter gene, electrophoretic mobility shift, kinase inhibitor assays, and in vitro kinase assay showed that ascochlorin inhibits MMP-9 gene expression by suppressing activation of the nuclear transcription factor activator protein-1 (AP-1) via the extracellular signal-regulated kinase 1 and 2 pathway. The AP-1 family member most specifically affected by ascochlorin was Fra-1. Ascochlorin did not affect the activation of the c-Jun N-terminal or p38 kinase pathways. Moreover, transfection of Caki-1 cells with AP-1 decoy oligodeoxynucleotides resulted in the suppression of phorbol 12-myristate 13-acetate-induced MMP-9 expression and invasion. In conclusion, ascochlorin represents a unique natural anti-tumor compound that specifically inhibits MMP-9 activity through suppression of AP-1-dependent induction of MMP-9 gene expression.
authors.affiliation: Department of Pathology and Department of Obstetrics and Gynecology, College of Medicine, Catholic University of Daegu, Daegu 705-034, Korea.
authors.forename: Sahyun
authors.initials: S
authors.lastname: Hong
authors.forename: Kwan-Kyu
authors.initials: KK
authors.lastname: Park
authors.forename: Junji
authors.initials: J
authors.lastname: Magae
authors.forename: Kunio
authors.initials: K
authors.lastname: Ando
authors.forename: Tae-Sung
authors.initials: TS
authors.lastname: Lee
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Kwak
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000475:Alkenes / Q000494:pharmacology*; D020816:Amino Acid Motifs; D001667:Binding, Competitive; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008954:Models, Biological; D008956:Models, Chemical; D010636:Phenols / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate; D008063:Thioctic Acid / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000475:Alkenes; D010636:Phenols; D018808:Transcription Factor AP-1; D008063:Thioctic Acid; D003907:Dexamethasone; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; C415745:ascochlorin