Glycitein inhibits glioma cell invasion through down-regulation of MMP-3 and MMP-9 gene expression
Glycitein inhibits glioma cell invasion through down-regulation of MMP-3 and MMP-9 gene expression
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DOI：
10.1016/j.cbi.2010.02.037
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发表时间：
2010-04-15
影响因子：
5.1
通讯作者：
Kim, Hee-Sun
中科院分区：
文献类型：
--
作者：
Lee, Eun-Jung;Kim, So-Young;Kim, Hee-Sun
基质金属蛋白酶（MMPs）是一种锌依赖性内肽酶，在恶性胶质瘤细胞的侵袭和血管生成中起关键作用。因此，抑制MMPs被认为是一种有前途的脑肿瘤治疗策略。在本研究中，我们发现，黄豆黄素，细菌代谢产物的黄豆黄素，抑制MMP-3和MMP-9的表达在启动子，mRNA和蛋白质水平在PMA刺激的U87 MG人星形胶质瘤细胞。明胶酶谱显示黄豆黄素抑制PMA诱导的U87 MG细胞MMP-9的分泌。随后的Matrigel侵袭测定显示，大豆黄素抑制胶质瘤细胞的体外侵袭性，这可能至少部分是由于大豆黄素介导的MMP-3和MMP-9的抑制。支持这一点，治疗MMP-3或MMP-9特异性抑制剂显着抑制PMA诱导的胶质瘤细胞的侵袭。进一步的机制研究表明，黄豆黄素抑制NF-κ B和AP-1的DNA结合和转录活性，NF-κ B和AP-1是MMP-3或MMP-9基因表达的重要转录因子。此外，黄豆黄素抑制PMA诱导的三种类型的MAP激酶的磷酸化，这是在神经胶质瘤细胞中MMP基因表达和NF-κ B和AP-1活性的上游信号分子。因此，黄豆黄素抑制MMP-3和MMP-9的表达可能对控制恶性胶质瘤的侵袭性具有治疗潜力。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a pivotal role in invasion and angiogenesis of malignant glioma cells. Therefore, the inhibition of MMPs has been suggested to be a promising therapeutic strategy for brain tumors. In the present study, we found that glycitein, a bacterial metabolite of the isoflavone glycitin, inhibits the expression of MMP-3 and MMP-9 at promoter, mRNA, and protein levels in PMA-stimulated U87MG human astroglioma cells. In addition, gelatin zymography showed that glycitein inhibited the PMA-induced MMP-9 secretion in U87MG cells. A subsequent Matrigel invasion assay revealed that glycitein suppresses the in vitro invasiveness of glioma cells, which may be at least partly due to the glycitein-mediated inhibition of MMP-3 and MMP-9. In support of this, treatment of MMP-3- or MMP-9-specific inhibitor significantly suppressed PMA-induced invasion of glioma cells. Further mechanistic studies revealed that glycitein inhibits the DNA binding and transcriptional activities of NF-kappa B and AP-1, which are important transcription factors for MMP-3 or MMP-9 gene expression. Furthermore, glycitein suppresses PMA-induced phosphorylation of three types of MAP kinases, which are upstream signaling molecules in MMP gene expressions and NF-kappa B and AP-1 activities in glioma cells. Therefore, the inhibition of MMP-3 and MMP-9 expression by glycitein may have therapeutic potential for controlling invasiveness of malignant gliomas. (C) 2010 Elsevier Ireland Ltd. All rights reserved.