Cofilin drives cell-invasive and metastatic responses to TGF-β in prostate cancer.
Cofilin drives cell-invasive and metastatic responses to TGF-β in prostate cancer.
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DOI：
10.1158/0008-5472.can-13-3058
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发表时间：
2014-04-15
期刊：
影响因子：
11.2
通讯作者：
Kyprianou N
中科院分区：
文献类型：
--
作者：
Collazo J;Zhu B;Larkin S;Martin SK;Pu H;Horbinski C;Koochekpour S;Kyprianou N
Cofilin（CFL）是一种F-肌动蛋白切断蛋白，其在细胞骨架重组和丝状伪足形成中是必需的，其驱动细胞迁移。CFL的结合和F-肌动蛋白的切断由Ser3磷酸化控制，但这一步骤在癌细胞侵袭和转移过程中对细胞迁移的贡献尚不清楚。在这项研究中，我们解决了前列腺癌细胞中的问题，包括对TGF-β的反应，TGF-β是迁移的关键调节因子。在表达野生型CFL的细胞中，TGF-β处理增加LIMK-2活性和cofilin磷酸化，减少丝状伪足形成。相反，组成型活性CFL（SerAla）促进丝状足形成和TGF-β介导的细胞迁移。值得注意的是，在前列腺癌上皮细胞和癌症相关成纤维细胞的共培养物中，活性CFL响应微环境中的TGF-β而促进侵袭性迁移。此外，组成型活性CFL提高了前列腺癌细胞在体内的转移能力。我们发现，在小鼠前列腺肿瘤模型中，活性CFL的水平与转移相关，在人前列腺癌中，CFL表达在转移性肿瘤中显著增加。我们的研究结果表明，肌动蛋白切断蛋白CFL协调对侵袭性癌症迁移和转移所需的TGF-β的反应。
Cofilin (CFL) is an F-actin–severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study, we addressed the question in prostate cancer cells, including the response to TGF-β, a critical regulator of migration. In cells expressing wild-type CFL, TGF-β treatment increased LIMK-2 activity and cofilin phosphorylation, decreasing filopodia formation. Conversely, constitutively active CFL (SerAla) promoted filipodia formation and cell migration mediated by TGF-β. Notably, in cocultures of prostate cancer epithelial cells and cancer-associated fibroblasts, active CFL promoted invasive migration in response to TGF-β in the microenvironment. Further, constitutively active CFL elevated the metastatic ability of prostate cancer cells in vivo. We found that levels of active CFL correlated with metastasis in a mouse model of prostate tumor and that in human prostate cancer, CFL expression was increased significantly in metastatic tumors. Our findings show that the actin-severing protein CFL coordinates responses to TGF-β that are needed for invasive cancer migration and metastasis.