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

被引:119
作者
Hong, S
Park, KK
Magae, J
Ando, K
Lee, TS
Kwon, TK
Kwak, JY
Kim, CH
Chang, YC
机构
[1] Catholic Univ Daegu, Coll Med, Dept Pathol, Taegu 705034, South Korea
[2] Catholic Univ Daegu, Coll Med, Dept Obstet & Gynecol, Taegu 705034, South Korea
[3] Inst Res & Innovat, Dept Biotechnol, Kashiwa, Chiba 2770861, Japan
[4] NRL Pharma Inc, Kawasaki, Kanagawa 2130012, Japan
[5] Keimyung Univ, Sch Med, Dept Immunol, Taegu 700712, South Korea
[6] Dong A Univ, Med Res Ctr Canc Mol Therapy, Pusan 602714, South Korea
[7] Dongguk Univ, Coll Oriental Med, Natl Res Lab Gycobiol, Korean Minist Sci & Technol, Kyungbuk 780714, South Korea
关键词
D O I
10.1074/jbc.M413985200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:25202 / 25209
页数:8
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