Nimbolide suppresses non-small cell lung cancer cell invasion and migration via manipulation of DUSP4 expression and ERK1/2 signaling
Nimbolide suppresses non-small cell lung cancer cell invasion and migration via manipulation of DUSP4 expression and ERK1/2 signaling
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DOI：
10.1016/j.biopha.2017.05.072
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发表时间：
2017-08-01
影响因子：
7.5
通讯作者：
Sun, Shenghua
中科院分区：
文献类型：
--
作者：
Lin, Hua;Qiu, Shiyang;Sun, Shenghua
宁波利特在治疗人类疾病方面发挥着重要作用。近年来，宁波利特的抗癌作用越来越受到人们的重视。然而，尼波利特在非小细胞肺癌(NSCLC)中的作用仍不清楚。在本研究中，我们发现尼莫列特以剂量依赖的方式抑制非小细胞肺癌细胞的侵袭和迁移。此外，尼莫列特剂量依赖性地抑制ERK1/2的激活，降低Snail和MMP3的表达，增加E-cadherin的表达。此外，我们还发现尼莫列特可上调DUSP4的表达。DUSP4基因敲除可减弱尼莫利特对细胞侵袭、迁移和ERK1/2激活的抑制作用。我们还发现DUSP4基因敲除抑制了宁波利特对MMP3、Snail和E-cadherin表达的影响。综上所述，我们的研究表明，尼波利特治疗可以上调DUSP4的表达，从而抑制ERK1/2的激活。Nimbolide通过抑制ERK1/2通路减少MMP3和Snail的表达，增加E-cadherin的表达，最终抑制NSCLC细胞的侵袭和迁移。因此，Nimbolide可能通过调控ERK1/2信号转导和DUSP4的表达，成为抑制NSCLC侵袭转移的新药。(C)2017年爱思唯尔·马森公司。版权所有。
Nimbolide plays an important role in treating human diseases. In these years, the anticancer property of nimbolide has been paid more and more attention. However, the role of nimbolide in nonsmall cell lung cancer (NSCLC) remains unclear. In this study, we found that nimbolide treatment suppressed the invasion and migration of NSCLC cells, in a dose-dependent manner. Moreover, nimbolide treatment dose-dependently inhibited ERK1/2 activation, decreased Snail and MMP3 expression, and increased E-cadherin expression. Further, we found that nimbolide treatment upregulated DUSP4 expression. DUSP4 knockdown attenuated nimbolide-mediated inhibition of cell invasion, migration and ERK1/2 activation. We also found that DUSP4 knockdown suppressed the effect of nimbolide on MMP3, Snail and E-cadherin expression. Taken together, our study demonstrates that nimbolide treatment can upregulate the expression of DUSP4, thus inhibiting ERK1/2 activation. Inhibition of ERK1/2 pathway by nimbolide decreases MMP3 and Snail expression, and increases E-cadherin expression, which finally inhibits NSCLC cell invasion and migration. Therefore, nimbolide may act as a novel drug to inhibit NSCLC invasion and metastasis through manipulation of ERK1/2 signaling and DUSP4 expression. (C) 2017 Elsevier Masson SAS. All rights reserved.