Journal
CANCER RESEARCH
Volume 70, Issue 22, Pages 9118-9128Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-1246
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Funding
- National Natural Science Foundation of China [30772476, 30873084, 30888003]
- Science and Technology Planning Project of Guangdong Province [2008A030201010]
- National Basic Research Program of China [S2010051025]
- National High Technology Research and Development Program of China [2006AA02A404]
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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.
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