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J. Biol. Chem., Vol. 280, Issue 26, 25202-25209, July 1, 2005

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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^*

SaHyun Hong, Kwan-Kyu Park, Junji Magae¶, Kunio Ando¶, Tae-Sung Lee||, Taeg Kyu Kwon**, Jong-Young Kwak, Cheorl-Ho Kim, and Young-Chae Chang¶¶

From the Department of Pathology and ^||Department of Obstetrics and Gynecology, College of Medicine, Catholic University of Daegu, Daegu, 705-034, Korea, Department of Biotechnology, Institute of Research and Innovation, Kashiwa 277-0861, Japan, ^¶NRL Pharma Inc., Kawasaki 213-0012, Japan, ^**Department of Immunology, Keimyung University School of Medicine, Daegu 700-712, Korea, Medical Research Center for Cancer Molecular Therapy, Dong-A University, Busan 602-714, Korea, and National Research Laboratory for Glycobiology, Korean Ministry of Science and Technology, College of Oriental Medicine, Dongguk University, Kyungbuk 780-714, Korea

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.

Received for publication, December 13, 2004 , and in revised form, April 15, 2005.

^* This work was supported by Korea Research Foundation Grant KRF-2002-005-C00016. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶¶ To whom correspondence should be addressed: Dept. of Pathology, College of Medicine, Catholic University of Daegu, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu 705-034, Korea. Tel.: 82-53-650-4848, Fax: 82-53-650-4834, E-mail: ycchang{at}cu.ac.kr.

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