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Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion

Oncogene volume 33, pages 539–549 (2014)Cite this article

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Abstract

Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacological or RNA interference-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRCY416). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared with either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.

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Acknowledgements

We gratefully acknowledge Dr Maureen Murphy and Dr Timothy Yen for helpful discussions and critical review of this manuscript. We also thank Dr Maureen Murphy for providing access to the Guava EasyCyte system, and Dr Greg Enders for providing access to the Nikon Eclipse microscope. This work was supported by R01 CA136596, Tobacco Settlement funding from the State of Pennsylvania and Fox Chase Cancer Center via institutional support of the Keystone Program in Personalized Risk and Prevention (to DCC); Ovarian Cancer Research Fund Program of Excellence Award (to TVD); Ovarian SPORE P50 CA083638 (Project 4 to DCC, AKG and EAG and Pilot Award to TVD); R01 CA63366 (to EAG); R01 CA140323 (to AKG); and the Fox Chase Cancer Center Core Grant NCI P30 CA006927. The following Fox Chase Cancer Facilities were used: Laboratory Animal, Transgenic, Cell Culture, Biological Imaging, Histopathology, Biosample Repository and Biostatistics and Bioinformatics.

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Authors and Affiliations

  1. Women’s Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    T-V Do, F Xiao, L E Bickel, H B Pathak, C Howe, R J Schilder, A K Godwin & D C Connolly

  2. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    T-V Do, H B Pathak & A K Godwin

  3. Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    F Xiao, S W O'Brien, M Maglaty, E A Golemis & D C Connolly

  4. Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA

    A J Klein-Szanto

  5. Transgenic Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    X Hua

  6. Department of Translational Medicine, Millennium Pharmaceuticals Inc., Cambridge, MA, USA

    J A Ecsedy

  7. Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    S Litwin

  8. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA

    R J Schilder

  9. Department of Gynecologic Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA

    R J Schilder

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  1. T-V Do
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Do, TV., Xiao, F., Bickel, L. et al. Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion. Oncogene 33, 539–549 (2014). https://doi.org/10.1038/onc.2012.632

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