Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms

• Published in: Carcinogenesis (New York) 2007-05, Vol.28 (5), p.1104-1110
• Main Authors: Cho, Hyun-Ji, Kang, Jeong Han, Kwak, Jong-Young, Lee, Tae-Sung, Lee, In-Seon, Park, Nam Gyu, Nakajima, Hiroo, Magae, Junji, Chang, Young-Chae
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Enzymologic; Genes, ras; Humans; MAP Kinase Signaling System; Matrix Metalloproteinase 9 - genetics; Medical sciences; raf Kinases - metabolism; Rats; Sesquiterpenes - pharmacology; Signal Transduction; Tetradecanoylphorbol Acetate; Transcription Factor AP-1 - metabolism; Transcriptional Activation; Tumor Cells, Cultured; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgl217

The expression of matrix metalloproteinase-9 (MMP-9) has been implicated in the invasion and metastasis of cancer cells. Here, we found that an antitumor antibiotic, ascofuranone, inhibits invasion and MMP-9 induction induced by phorbol myristate acetate (PMA) in human cell lines. Ascofuranone also inhibits the protein expression and transcription of MMP-9 induced by tumor necrosis factor-α. The inhibition of MMP-9 induction was observed in human cancer cell lines as well as primary rat mesangial cells. Furthermore, as evidenced by MMP-9 promoter and electrophoretic mobility shift assays, ascofuranone specifically inhibited MMP-9 gene expression by blocking PMA-stimulated activation of activator protein-1 (AP-1). In addition, ascofuranone suppressed PMA-induced phosphorylation of Ras, Raf, MEK and extracellular signal-regulated kinase (ERK), upstream factors involved in AP-1activation, whereas the phosphorylation of p38 and JNK/mitogen-activated protein kinase was not affected by ascofuranone, suggesting that the primary target of ascofuranone for suppression of the AP-1 induction is present in upstream of ERK signaling pathway. These results suggest that the suppression of MMP-9 expression, at least in part, contributes to the antitumor activity of ascofuranone.