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Carcinogenesis Advance Access published online on November 17, 2006

Carcinogenesis, doi:10.1093/carcin/bgl217
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 10, 2006
Revised October 9, 2006
Accepted November 2, 2006

CARCINOGENESIS

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

Hyun-Ji Cho 1, Jeong Han Kang 1, Jong-Young Kwak 2, Tae-Sung Lee 3, In-Seon Lee 4, Nam-Gyu Park 5, Hiroo Nakajima 6, Junji Magae 7, and Young-Chae Chang 1 *

1 Department of Pathology, Catholic University of Daegu School of Medicine, Daegu 705-718, Korea
2 Medical Research Center (MRC) for Cancer Molecular Therapy, Dong-A University, Busan, Korea
3 Department of Obstetrics and Gynecology, Catholic University of Daegu School of Medicine, Daegu 705-718, Korea
4 The Center for Traditional Microorganism Resources (TMR), Keimyung University, Daegu 704-701, Korea
5 Department of Biotechnology and Bioengineering and Bioengineering, Pukyong National University, Busan 608-737, Korea
6 Department of Endocrine, Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan
7 Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa 277-0861, Japan

* To whom correspondence should be addressed.
Young-Chae Chang, E-mail: ycchang{at}cu.ac.kr


   Abstract

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-{alpha}. 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 ERK, upstream factors involved in AP-1activation, while the phosphorylation of p38 and JNK/MAPK was not affected by ascofuranone, suggesting that the primary target of ascofuranone for suppression of the AP-1 inudction 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 anti-tumor activity of ascofuranone.

Keywords: Ascofuranone; Matrix Metalloproteinase-9; Activator Protein-1; Osteosarcoma; Tumor invasion.
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