Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-β1/Smad3 signaling pathway
Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-β1/Smad3 signaling pathway
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DOI：
10.3892/or.2016.4661
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发表时间：
2016-05-01
期刊：
影响因子：
4.2
通讯作者：
Wang, Ruozheng
中科院分区：
文献类型：
--
作者：
Da, Chunli;Liu, Yuting;Wang, Ruozheng
上皮-间质转化（EMT）是癌症转移中的一个关键细胞过程，在此过程中上皮极化细胞变成活动的间质细胞。由于转化生长因子-β (TGF-β) 是 EMT 的有效诱导剂，因此阻断 TGF-β/Smad 信号传导已成为一种有前景的癌症治疗方法。 Nobiletin 是一种来自扁柑橘的多甲氧基黄酮类化合物，已被证明对癌症治疗有价值，但其机制仍不清楚。本研究采用肺腺癌A549和H1299细胞评价川陈皮素对TGF-β1诱导的EMT的影响。川陈皮素在体外成功抑制TGF-f31诱导的EMT、迁移、侵袭和粘附，并伴有MMP-2、MMP-9、p-Src、p-FAK、 p-paxillin、Snail、Slug、Twist 和 ZEB1 表达。 Nobiletin 抑制 Smad 的转录活性，但不改变 TGF-β 1 诱导的 Smad 磷酸化状态或易位。此外，Smad3 在 TGF-β 1 刺激的 EMT 中是必需的。 Smad3 过度表达显着损害川陈皮素逆转 TGF-β 1 诱导的 EMT 的能力。在体内，川陈皮素抑制裸鼠肺部转移结节的生长。此外，IVIS 成像和免疫组织化学分析显示，川陈皮素可抑制 A549-Luc 异种移植小鼠的肿瘤生长并逆转 EMT。总的来说，数据表明川陈皮素通过灭活 TGF-β 1/Smad3 信号传导来预防 EMT。
Epithelial-mesenchymal transition (EMT) is a critical cellular process in cancer metastasis, during which epithelial polarized cells become motile mesenchymal cells. Since transforming growth factor-beta (TGF-beta) is a potent inducer of EMT, blocking of TGF-beta/Smad signaling has become a promising cancer therapy. Nobiletin, a polymethoxy flavonoid from Citrus depressa, has been shown to be valuable for cancer treatment, yet the mechanism remains unclear. In the present study, lung adenocarcinoma A549 and H1299 cells were used to evaluate the effect of nobiletin on EMT induced by TGF-beta 1. Nobiletin successfully inhibited TGF-f31-induced EMT, migration, invasion and adhesion in vitro, accompanied by attenuation of MMP-2, MMP-9, p-Src, p-FAK, p-paxillin, Snail, Slug, Twist and ZEB1 expression. Nobiletin inhibited the transcriptional activity of Smads without changing the phosphorylation status or translocation of Smads induced by TGF-beta 1. Moreover, Smad3 is requisite in TGF-beta 1-stimulated EMT. Smad3 overexpression meaningfully impaired the ability of nobiletin to reverse TGF-beta 1-induced EMT. In vivo, nobiletin prohibited the growth of metastatic nodules in the lungs of nude mice. Moreover, nobiletin inhibited tumor growth and reversed EMT in mice bearing A549-Luc xenografts, as revealed by IVIS imaging and immunohistochemical analysis. Collectively, the data suggest that nobiletin prevents EMT by inactivating TGF-beta 1/Smad3 signaling.