Down-Regulation of MMP-2 Through the p38 MAPK-NF-κB-Dependent Pathway by Aloe-Emodin Leads to Inhibition of Nasopharyngeal Carcinoma Cell Invasion
Down-Regulation of MMP-2 Through the p38 MAPK-NF-κB-Dependent Pathway by Aloe-Emodin Leads to Inhibition of Nasopharyngeal Carcinoma Cell Invasion
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DOI：
10.1002/mc.20652
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发表时间：
2010-09-01
影响因子：
4.6
通讯作者：
Chen, Shih-Shun
中科院分区：
文献类型：
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作者：
Lin, Meng-Liang;Lu, Yao-Cheng;Chen, Shih-Shun
芦荟大黄素（Aloe-emodin，AE）是从掌叶大黄（Rheumpalmatum）根茎中提取的一种有效成分，对多种肿瘤细胞具有抗增殖作用。然而，AE抑制鼻咽癌（NPC）细胞侵袭的潜在机制仍不清楚。本研究的结果表明，用生长抑制浓度的AE处理NPC细胞，导致细胞周期停滞在S-G（2）/M期。免疫共沉淀和小干扰RNA（siRNA）的研究表明，AE诱导的细胞周期阻滞在NPC细胞与细胞周期蛋白B1结合细胞周期蛋白依赖性激酶1的水平增加。AE通过抑制基质金属蛋白酶-2（MMP-2）的表达来抑制鼻咽癌细胞的侵袭。p38丝裂原活化蛋白激酶（MAPK）siRNA、抑制剂4-（4-Fluorophenyl）-2-[4-（methylsulfinyl）-phenyl]-5-（4-pyridyl）-1H-imidazole（SB 203580）和AE可抑制MMP-2启动子活性和细胞侵袭，而JNK siRNA和抑制剂1，9-pyrazoloanthrone则不抑制MMP-2启动子活性和细胞侵袭。用AE、SB 203580、NF-κ B抑制剂N-对甲苯磺酰基-L-苯丙氨酸氯甲基酮（TPCK）和吡咯烷二硫代氨基甲酸酯（PDTC）处理或用p38 MAPK siRNA转染显著抑制NF-κ B转录活性。此外，TPCK和PDTC处理抑制MMP-2的表达和启动子活性，从而显着抑制细胞侵袭活性。通过SB 203580和NF-κ B异位表达减弱p38 MAPK活性，进一步证实了NF-κ B介导的MMP-2功能中p38 MAPK活性的参与。总的来说，我们的结果表明，AE通过抑制MMP-2的表达通过p38 MAPK-NF-κ B信号通路抑制鼻咽癌细胞的侵袭。(C)2010 Wiley-Liss，Inc.
Aloe-emodin (AE), extracted from the rhizome of Rheum palmatum, has an anti-proliferative effect on different human cancer cell lines. Nonetheless, the underlying mechanism by which AE inhibits nasopharyngeal carcinoma (NPC) cell invasion is still unclear. The results of this study show that treatment of NPC cells with growth suppressive concentrations of AE caused cell cycle arrest at the S-G(2)/M phase. Coimmunoprecipitation and small interfering RNA (siRNA) studies demonstrated that AE-induced cell cycle arrest in NPC cells was associated with increasing levels of cyclin B1 bound to cyclin-dependent kinase 1. The inhibition of NPC cell invasion by AE was evidenced through the suppression of matrix metalloproteinases-2 (MMP-2) expression. MMP-2 promoter activity and cell invasion were inhibited by p38 mitogen-activated protein kinase (MAPK) siRNA, inhibitor 4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)-phenyl]-5-(4-pyridyl)-1H-imidazole (SB203580), and AE, but not by JNK siRNA and inhibitor 1,9-pyrazoloanthrone. Treatment with AE, SB203580, NF-kappa B inhibitors N-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and pyrrolidine dithiocarbamate (PDTC) or transfection with p38 MAPK siRNA significantly inhibited NF-kappa B transcriptional activity. In addition, TPCK and PDTC treatment inhibited the expression and promoter activity of MMP-2 and thereby significantly inhibited cell invasion activity. The involvement of p38 MAPK activity in NF-kappa B-mediated MMP-2 function was further confirmed through the attenuation of p38 MAPK by SB203580 and NF-kappa B ectopic expression. Collectively, our results indicate that AE inhibits invasion of NPC cells by suppressing the expression of MMP-2 via the p38 MAPK-NF-kappa B signaling pathway. (C) 2010 Wiley-Liss, Inc.