Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA.
Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA.
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斑蝥素通过加速 MMP2 mRNA 的降解来抑制胰腺癌细胞的侵袭
DOI：
10.1038/srep11836
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发表时间：
2015-07-02
影响因子：
4.6
通讯作者：
Li W
中科院分区：
文献类型：
--
作者：
Shen M;Wu MY;Chen LP;Zhi Q;Gong FR;Chen K;Li DM;Wu Y;Tao M;Li W
斑泻素是一种中药有效成分，是一种有效的、选择性的蛋白磷酸酶2A(PP2A)抑制剂，在细胞周期调控、细胞凋亡和细胞命运决定中发挥着重要作用。本研究通过多种途径抑制胰腺癌细胞的侵袭能力，下调基质金属蛋白酶2的表达，包括ERK、JNK、PKC、NF-κB和β-Catenin。有趣的是，在用PP2A抑制剂处理后，MMP2启动子的转录活性增加，这表明参与了转录后机制。通过信使核糖核酸稳定性实验，我们发现斑泻素处理后MMP2信使核糖核酸的降解加速。基因芯片分析表明，参与3‘→5’衰变途径的多个基因表达上调，尤其是参与胞质去烯化的基因。进一步证明这些基因的上调是通过ERK、JNK、PKC、NF-κB和β-连环蛋白途径来实现的。PARN、RHAU和Cnot7是参与胞质去烯化的三个关键成员，它们的敲除减弱了MMP2的下调。因此，我们提出了斑泻素和其他PP2A抑制剂通过细胞质去烯化增加MMP2 mRNA的降解来抑制侵袭的机制。
Cantharidin is an active constituent of mylabris, a traditional Chinese medicine and is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in cell cycle control, apoptosis and cell-fate determination. In the present study, we found that cantharidin repressed the invasive ability of pancreatic cancer cells and downregulated matrix metalloproteinase 2 (MMP2) expression through multiple pathways, including ERK, JNK, PKC, NF-κB and β-catenin. Interestingly, transcriptional activity of the MMP2 promoter increased after treatment with PP2A inhibitors, suggesting the involvement of a posttranscriptional mechanism. By using an mRNA stability assay, we found accelerated degradation of MMP2 mRNA after treatment of cantharidin. Microarray analyses revealed that multiple genes involved in the 3'→5' decay pathway were upregulated, especially genes participating in cytoplasmic deadenylation. The elevation of these genes were further demonstrated to be executed through ERK, JNK, PKC, NF-κB and β-catenin pathways. Knockdown of PARN, RHAU and CNOT7, three critical members involved in cytoplasmic deadenylation, attenuated the downregulation of MMP2. Hence, we present the mechanism of repressed invasion by cantharidin and other PP2A inhibitors through increased degradation of MMP2 mRNA by elevated cytoplasmic deadenylation.
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