Abstract
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.
Highlights
The serine/threonine Aurora kinase family, including Aurora-A, Aurora-B, and Aurora-C, play an important role in ensuring genetic stability in cell division [1]
Cell migration assay was performed, and we found that Aurora A (Aur-A) enhanced cell migration significantly in all three cell lines (Fig. 1A)
Aur-A–induced actin reorganization was totally blocked by wortmannin (100 nmol/L; Fig. 5D). These results suggest that SSH1 as well as phosphatidylinositol 3-kinase (PI3K) play a critical role in Aur-A–induced cofilin activity and cell migration
Summary
The serine/threonine Aurora kinase family, including Aurora-A, Aurora-B, and Aurora-C, play an important role in ensuring genetic stability in cell division [1]. Aur-A is physically associated with hBora, which in turn promotes activation of Polo-like kinase 1, Authors' Affiliations: 1State Key Laboratory of Oncology in South China, Cancer Center, and 2Sun Yat-sen Institute of Hematology, Sun Yat-sen University; Departments of 3Radiology and 4Hematology, Third Affiliated Hospital of Sun Yat-sen University; and 5MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China. Overexpression of Aur-A leads to centrosome amplification and subsequent formation of multipolar spindle structures, causing genetic instability or aneuploidy [4]. Our data showed that Aur-A increases laryngeal cancer cell migration [8]. The precise role of Aur-A in cancer invasion and metastasis remains largely unknown
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