Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway
Oroxylin A inhibits matrix metalloproteinase-2/9 expression and activation by up-regulating tissue inhibitor of metalloproteinase-2 and suppressing the ERK1/2 signaling pathway
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Oroxylin A 通过上调金属蛋白酶-2 的组织抑制剂并抑制 ERK1/2 信号通路来抑制基质金属蛋白酶-2/9 的表达和激活。
DOI：
10.1016/j.toxlet.2011.12.022
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发表时间：
2012-03-25
影响因子：
3.5
通讯作者：
Guo, Qinglong
中科院分区：
文献类型：
--
作者：
Lu, Zhijian;Lu, Na;Guo, Qinglong
基质金属蛋白酶（matrix metalloproteinases，MMPs）在肿瘤细胞的侵袭和迁移过程中起重要作用。本研究采用体外和体内实验方法，研究了从紫藤中提取的主要黄酮类化合物之一--我们发现，oroxylin A可以抑制细胞粘附，侵袭和迁移的浓度依赖性的方式。明胶酶谱、实时荧光定量PCR和蛋白质印迹分析显示，木脂素A可降低MMP-2和MMP-9的活性和表达水平。进一步阐明其作用机制表明，木脂素A可增加MMP-2的内源性抑制因子TIMP-2的表达，并抑制佛波醇-12-肉豆蔻酸酯-13-乙酸酯（PMA）诱导的蛋白激酶C δ转位（PKC δ），细胞外信号调节激酶（ERK 1/2）的磷酸化和转录因子激活蛋白-1（AP-1）的结合活性其是MMP-9表达的上游信号分子。我们的研究结果还表明，在体内的小鼠黑色素瘤细胞B16-F10的肺转移的抑制。因此，我们提出，oroxylin A可能被开发为用于治疗癌症转移的治疗潜在候选物。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In this study, we used in vitro and in vivo assays to examine the inhibitory effects of oroxylin A, one of the main bioactive flavonoid extracted from Scutellaria radix, on the human breast carcinoma cell MDA-MB-231 invasion and migration. We found that oroxylin A can suppress cell adhesion, invasion and migration in a concentration-dependent manner. Moreover, oroxylin A led to the reduction of the activity and expression levels of MMP-2 and MMP-9 in gelatin zymography, real-time PCR and western blotting analysis. Further elucidation of the mechanism revealed that oroxylin A increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2), the endogenous inhibitor of MMP-2, and repressed the phorbol-12-myristate-13-acetate (PMA)-induced translocation of protein kinase C delta (PKC delta), phosphorylation of extracellular signal-regulated kinase (ERK1/2) and binding activity of the transcription factor activator protein-1 (AP-1) which are upstream signaling molecules in MMP-9 expression. Our results also indicated that oroxylin A inhibited the lung metastasis of murine melanoma cell B16-F10 in vivo. Therefore, we proposed that oroxylin A might be developed as a therapeutic potential candidate for the treatment of cancer metastasis. (C) 2012 Elsevier Ireland Ltd. All rights reserved.