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首页> 外文期刊>Journal of Cellular Physiology >Involvement of receptor tyrosine phosphatase DEP-1 mediated PI3K-cofilin signaling pathway in sorafenib-induced cytoskeletal rearrangement in hepatoma cells.
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Involvement of receptor tyrosine phosphatase DEP-1 mediated PI3K-cofilin signaling pathway in sorafenib-induced cytoskeletal rearrangement in hepatoma cells.

机译：参与受体酪氨酸磷酸酶DEP-1PI3K-cofilin介导的信号通路sorafenib-induced细胞骨架重排在肝癌细胞。

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Sorafenib is a multikinase inhibitor that has been reported to induce cell growth inhibition through the Raf-MAPK signaling pathway. We now report that Sorafenib treatment of Hep3B and PLC/PRF/5 human hepatoma cells also results in morphological changes and cell detachment in culture. Actin cytoskeletal analysis of Sorafenib-exposed Hep3B cells showed a loss of polymerized F-actin and a concomitant increase in unpolymerized G-actin, implying that Sorafenib-induced cell shape changes may be related to actin cytoskeletal rearrangement by inhibiting actin polymerization. Cofilin, an actin depolymerization factor, was found to be dephosphorylated and thus activated by Sorafenib, consistent with the observed increase in unpolymerized G-actin. In examining likely mechanisms, we found that Sorafenib induced activation of the cofilin phosphatase Slingshot 1 (SSH-1), since endogenous SSH-1 from Sorafenib-treated Hep3B cells was able to dephosphorylate cofilin in a concentration dependent manner. The activation of SSH-1 by Sorafenib is probably regulated by the PI3K pathway, since Sorafenib can induce PI3K and its substrate Akt phosphorylation, and both PI3K inhibitors Ly294002 and wortmannin antagonized Sorafenib-mediated cofilin dephosphorylation. Furthermore, we found that Sorafenib induced c-Met phosphorylation at Tyr-1349 but not Tyr-1234, which is probably mediated by inhibition of receptor tyrosine phosphatase density enhanced phosphatase-1 (DEP-1). Our data provide evidence that besides inhibition of the Raf-MAPK pathway, Sorafenib might also regulate hepatoma cell growth via alteration of receptor-mediated cytoskeletal rearrangement.
机译：索拉非尼是一种multikinase抑制剂据报道,诱导细胞生长抑制Raf-MAPK信号通路。索拉非尼治疗Hep3B和PLC /脉冲重复频率/ 5人类肝癌细胞也导致形态变化和细胞分离文化。Sorafenib-exposed Hep3B细胞显示的损失聚合f -肌动蛋白和相应增加unpolymerized G-actin,暗示Sorafenib-induced细胞形状的变化与肌动蛋白细胞骨架重排抑制肌动蛋白聚合。肌动蛋白解聚因子,被发现脱去磷酸,从而激活索拉非尼,与观察到的增加保持一致unpolymerized G-actin。机制,我们发现索拉非尼诱导的激活cofilin磷酸酶弹弓1(SSH-1),因为内生SSH-1Sorafenib-treated Hep3B细胞能够脱去磷酸cofilin浓度依赖的方式。索拉非尼可能是PI3K的监管通路,因为索拉非尼可以诱导PI3K和它基质一种蛋白激酶磷酸化,PI3K抑制剂Ly294002和渥曼青霉素引起了Sorafenib-mediated cofilin去磷酸化。此外,我们发现索拉非尼诱导c-Met磷酸化酪氨酸- 1349但不是酪氨酸- 1234,这可能是由受体酪氨酸磷酸酶的抑制作用密度增强phosphatase-1 (DEP-1)。提供的证据表明,除了抑制Raf-MAPK通路,索拉非尼也可能调节通过改变肝癌细胞生长受体介导细胞骨架重排。

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