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首页> 外文期刊>Neoplasia: an international journal for oncology research >Kaempferol Suppresses Transforming Growth Factor-β1–Induced Epithelial-to-Mesenchymal Transition and Migration of A549 Lung Cancer Cells by Inhibiting Akt1-Mediated Phosphorylation of Smad3 at Threonine-179
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Kaempferol Suppresses Transforming Growth Factor-β1–Induced Epithelial-to-Mesenchymal Transition and Migration of A549 Lung Cancer Cells by Inhibiting Akt1-Mediated Phosphorylation of Smad3 at Threonine-179

机译：Kaempferol通过抑制Akt1介导的Smad3在Threonine-179，抑制转化生长因子-β1诱导的A549肺癌细胞的迁移和迁移

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Kaempferol, a natural dietary flavonoid, is well known to possess chemopreventive and therapeutic anticancer efficacy; however, its antimetastatic effects have not been mechanistically studied so far in any cancer model. This study was aimed to investigate the inhibitory effect and accompanying mechanisms of kaempferol on epithelial-to-mesenchymal transition (EMT) and cell migration induced by transforming growth factor-β1 (TGF-β1). In human A549 non–small lung cancer cells, kaempferol strongly blocked the enhancement of cell migration by TGF-β1–induced EMT through recovering the loss of E-cadherin and suppressing the induction of mesenchymal markers as well as the upregulation of TGF-β1–mediated matrix metalloproteinase-2 activity. Interestingly, kaempferol reversed TGF-β1–mediated Snail induction and E-cadherin repression by weakening Smad3 binding to the Snail promoter without affecting its C-terminus phosphorylation, complex formation with Smad4, and nuclear translocation under TGF-β1 stimulation. Mechanism study revealed that the phosphorylation of Smad3 linker region induced by TGF-β1 was required for the induction of EMT and cell migration, and selective downregulation of the phosphorylation of Smad3 at Thr179 residue (not Ser204, Ser208, and Ser213) in the linker region was responsible for the inhibition by kaempferol of TGF-β1–induced EMT and cell migration. Furthermore, Akt1 was required for TGF-β1–mediated induction of EMT and cell migration and directly phosphorylated Smad3 at Thr179, and kaempferol completely abolished TGF-β1–induced Akt1 phosphorylation. In summary, kaempferol blocks TGF-β1–induced EMT and migration of lung cancer cells by inhibiting Akt1-mediated phosphorylation of Smad3 at Thr179 residue, providing the first evidence of a molecular mechanism for the anticancer effect of kaempferol.
机译：Kaempferol，一种天然膳食类黄酮，众所周知，具有化学预防和治疗性抗癌效果;然而，到目前为止，它在任何癌症模型中都没有机械地研究其抗体效应。该研究旨在探讨Kaempferol对通过转化生长因子-β1（TGF-β1）诱导的上皮对间充质转换（EMT）和细胞迁移的抑制作用和伴随机制。在人类A549非小肺癌细胞中，Kaempferol通过回收E-Cadherin的丧失并抑制间充质标记物的诱导以及TGF-β1的上调以及TGF-β1的上调，强烈阻断了细胞迁移的增强。以及TGF-β1的上调介导的基质金属蛋白酶-2活性。有趣的是，Kaempferol通过削弱与蜗牛启动子的Smad3结合而逆转TGF-β1介导的蜗牛诱导和e-Cadherin抑制，而不影响其C-末端磷酸化，复杂地形成，在TGF-β1刺激下核易位。机制研究表明，由TGF-β1诱导的Smad3接头区域的磷酸化是EMT和细胞迁移的诱导所必需的，以及在接头区域中AT179残基（不是SER204，SER208和SER213）的SMAD3磷酸化的选择性下调对TGF-β1诱导的EMT和细胞迁移的Kaempferol负责抑制。此外，TGF-β1介导的EMT和细胞迁移诱导需要AKT1，并且在THR179上直接磷酸化SMAD3，并且Kaempferol完全废除TGF-β1诱导的AKT1磷酸化。总之，Kaempferol通过抑制THR179残基抑制SMAD3的Akt1介导的磷酸化而诱导TGF-β1诱导的EMT和肺癌细胞迁移，提供了kaempferol抗癌作用的分子机制的第一种证据。

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