Norcantharidin Suppresses Colon Cancer Cell Epithelial-Mesenchymal Transition by Inhibiting the αvβ6-ERK-Ets1 Signaling Pathway.
Norcantharidin Suppresses Colon Cancer Cell Epithelial-Mesenchymal Transition by Inhibiting the αvβ6-ERK-Ets1 Signaling Pathway.
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DOI：
10.1038/srep20500
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发表时间：
2016-02-05
影响因子：
4.6
通讯作者：
Niu J
中科院分区：
文献类型：
--
作者：
Peng C;Li Z;Niu Z;Niu W;Xu Z;Gao H;Niu W;Wang J;He Z;Gao C;Lin P;Agrez M;Zhang Z;Niu J
去甲斑秃(Norcantharidin，NCTD)是中国用药多年的有效抗癌药物，但其潜在作用机制尚不完全清楚。在本研究中，我们发现NCTD可以诱导结肠癌细胞的形态变化，导致从纺锤形到典型的圆形或椭圆形的转变，这表明了间质-上皮转化(MET)过程。接下来，我们研究了NCTD诱导MET过程的机制。通过Transwell实验，我们发现NCTD可以剂量依赖的方式抑制结肠癌细胞的迁移和侵袭能力。此外，NCTD还抑制整合素αvMMP6、β-3和MMP9的表达以及F-肌动蛋白的聚合，进一步支持了其对迁移和侵袭能力的抑制作用。α-v、β6、N-钙粘蛋白、波形蛋白和磷酸化ERK的表达降低，E-钙粘素的表达上调。我们证实，NCTD治疗后，磷酸化的Ets1显著下调。综上所述，我们的研究结果表明，NCTD可能通过抑制αv ERK6-β-Ets1信号通路来抑制结肠癌细胞的转导过程。这项研究揭示了NCTD逆转结肠癌EMT过程的部分机制。
Norcantharidin (NCTD) is an efficacious anti-cancer drug that has been used in China for many years, but its underlying mechanism of action is still not fully understood. In the present study, we found that NCTD could induce morphological changes in colon cancer cells, causing a transition from a spindle-shaped morphology to a typical round or oval shape, which was indicative of a mesenchymal-epithelial transition (MET) process. Next, we investigated the mechanism by which NCTD induced the MET process. Using a transwell assay, we found that NCTD could suppress the migratory and invasive ability of colon cancer cells in a dose-dependent manner. Moreover, NCTD suppressed the expression of integrin αvβ6, MMP-3, and MMP-9 as well as the polymerization of F-actin, further supporting its suppressive effect on migratory and invasive ability. Furthermore, the expression of αvβ6, N-cadherin, vimentin and phosphorylated ERK was decreased, while the expression of E-cadherin was up-regulated. We verified that phosphorylated Ets1 was down-regulated substantially after treatment with NCTD. Taken together, our data demonstrated that NCTD could inhibit the EMT process of colon cancer cells by inhibiting the αvβ6-ERK-Ets1 signaling pathway. This study revealed part of the mechanism through which NCTD could reverse the EMT process in colon cancer.