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
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
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DOI：
10.1074/jbc.m413985200
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发表时间：
2005-07-01
影响因子：
4.8
通讯作者：
Chang, YC
中科院分区：
文献类型：
--
作者：
Hong, S;Park, KK;Chang, YC
基质金属蛋白酶（MMPs）的表达与癌细胞的侵袭和转移有关。本文研究了抗坏血氯素（ascochlorin）对人肾癌（Caki-1）细胞中控制MMP-9表达的信号通路的调节作用。抗坏血氯素是一种来自真菌ascoyta viciae的丙烯酚抗肿瘤化合物。抗坏血氯降低Caki-1细胞的侵袭活性，抑制phorbol 12-肉豆蔻酸13-乙酸酯诱导的MMP-9表达和活性的增加，并呈剂量依赖性。报告基因、电泳迁移率、激酶抑制剂和体外激酶实验表明，抗坏血氯素通过胞外信号调节的激酶1和2途径抑制核转录因子激活蛋白1 （AP-1）的激活，从而抑制MMP-9基因的表达。受抗坏血氯胺影响最明显的AP-1家族成员是Fra-1。抗坏血氯胺不影响c-Jun n端或p38激酶途径的激活。此外，用AP-1诱捕物转染Caki-1细胞可抑制phorbol 12-肉豆蔻酸13-乙酸酯诱导的MMP-9表达和侵袭。综上所述，抗坏血氯素是一种独特的天然抗肿瘤化合物，通过抑制ap -1依赖性诱导MMP-9基因表达，特异性抑制MMP-9活性。
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.