Carcinogenesis Advance Access originally published online on November 17, 2006
Carcinogenesis 2007 28(5):1104-1110; doi:10.1093/carcin/bgl217
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Ascofuranone suppresses PMA-mediated matrix metalloproteinase-9 gene activation through the Ras/Raf/MEK/ERK- and Ap1-dependent mechanisms
Department of Pathology, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-718, Korea
1 Medical Research Center for Cancer Molecular Therapy, Dong-A University, Busan 602-714, Korea
2 Department of Obstetrics and Gynecology, Catholic University of Daegu School of Medicine, Daegu 705-718, Korea
3 The Center for Traditional Microorganism Resources, Keimyung University, Daegu 704-701, Korea
4 Department of Biotechnology and Bioengineering, Pukyong National University, Busan 608-737, Korea
5 Department of Endocrine, Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan
6 Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa 277-0861, Japan
* To whom correspondence should be addressed. Tel: +82 53 650 4848; Fax: +82 53 650 4834; Email: ycchang{at}cu.ac.kr
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-
. 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.
Abbreviations: AP-1, activator protein-1; DTT, dithiothreitol; EDTA, ethylenediaminetetraacetic acid; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; NF-
B, NF-kappaB; PMA, phorbol myristate acetate; TIMPs, tissue inhibitors of metalloproteinases; TNF-, tumor necrosis factor-
Received July 10, 2006; revised October 9, 2006; accepted November 2, 2006.
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