The Mitotic Kinase Aurora-A Induces Mammary Cell Migration and Breast Cancer Metastasis by Activating the Cofilin-F-actin Pathway
The Mitotic Kinase Aurora-A Induces Mammary Cell Migration and Breast Cancer Metastasis by Activating the Cofilin-F-actin Pathway
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有丝分裂激酶 Aurora-A 通过激活 Cofilin-F-actin 途径诱导乳腺细胞迁移和乳腺癌转移
DOI：
10.1158/0008-5472.can-10-1246
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发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Liu, Quentin
中科院分区：
文献类型：
--
作者：
Wang, Li-hui;Xiang, Jin;Liu, Quentin
有丝分裂激酶Aurora-A（Aur-A）是形成双极纺锤体和确保细胞分裂前染色体精确分离所必需的。Aur-A失调代表促进肿瘤形成的致癌事件。在这里，我们报告说，Aur-A促进乳腺癌转移。Aur-A过表达通过去磷酸化和激活cofilin促进肌动蛋白重组和聚合来增强乳腺细胞迁移。Cofilin敲低损害Aur-A驱动的细胞迁移和细胞膜突起。相反，激活的cofilin的过表达消除了Aur-A敲低对细胞迁移的影响。此外，Aur-A过度表达增加了cofilin磷酸酶Slingshot-1（SSH 1）的表达，有助于cofilin激活和细胞迁移。我们发现，磷脂酰肌醇3-激酶（PI 3 K）抑制阻断Aur-A诱导的cofilin去磷酸化，肌动蛋白重组和细胞迁移，这表明与PI 3 K信号转导的串扰和PI 3 K抑制在Aur-A失调的肿瘤中的潜在益处。此外，我们发现乳腺癌组织中Aur-A过表达和cofilin活性之间存在关联。我们的研究结果表明，cofilin-F-actin途径的激活有助于肿瘤细胞的迁移和转移增强的Aur-A，揭示了一个新的功能，有丝分裂Aur-A激酶在肿瘤的进展。Cancer Res; 70（22）; 9118-28. (C)2010年AACR。
The mitotic kinase Aurora-A (Aur-A) is required to form the bipolar spindle and ensure accurate chromosome segregation before cell division. Aur-A dysregulation represents an oncogenic event that promotes tumor formation. Here, we report that Aur-A promotes breast cancer metastasis. Aur-A overexpression enhanced mammary cell migration by dephosphorylation and activation of cofilin, which facilitates actin reorganization and polymerization. Cofilin knockdown impaired Aur-A-driven cell migration and protrusion of the cell membrane. Conversely, overexpression of activated cofilin abrogated the effects of Aur-A knockdown on cell migration. Moreover, Aur-A overexpession increased the expression of the cofilin phosphatase Slingshot-1 (SSH1), contributing to cofilin activation and cell migration. We found that phosphatidylinositol 3-kinase (PI3K) inhibition blocked Aur-A-induced cofilin dephosphorylation, actin reorganization, and cell migration, suggesting crosstalk with PI3K signaling and a potential benefit of PI3K inhibition in tumors with deregulated Aur-A. Additionally, we found an association between Aur-A overexpression and cofilin activity in breast cancer tissues. Our findings indicate that activation of the cofilin-F-actin pathway contributes to tumor cell migration and metastasis enhanced by Aur-A, revealing a novel function for mitotic Aur-A kinase in tumor progression. Cancer Res; 70(22); 9118-28. (C) 2010 AACR.