Aurora kinase A mediates epithelial ovarian cancer cell migration and adhesion.

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 (pSRC(Y416)). 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.

• Authors: T-V Do, F Xiao, L E Bickel, A J Klein-Szanto, H B Pathak, X Hua, C Howe, S W O'Brien, M Maglaty, J A Ecsedy, S Litwin, E A Golemis, R J Schilder, A K Godwin, D C Connolly
• Journal: Oncogene (Oncogene) Vol. 33 Issue 5 Pg. 539-49 (Jan 30 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 23334327 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents, Phytogenic
• Azepines
• MLN 8237
• Protein Kinase Inhibitors
• Pyrimidines
• RNA, Small Interfering
• src-Family Kinases
• Aurora Kinase A
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects, genetics)
• Aurora Kinase A (antagonists & inhibitors, genetics, metabolism)
• Azepines (pharmacology)
• Carcinoma, Ovarian Epithelial
• Cell Adhesion
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Movement
• Female
• Humans
• Mice
• Mitosis (drug effects)
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neoplasms, Glandular and Epithelial (enzymology, pathology)
• Ovarian Neoplasms (enzymology, pathology)
• Paclitaxel (pharmacology)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• RNA Interference
• RNA, Small Interfering (genetics)
• Xenograft Model Antitumor Assays
• src-Family Kinases (metabolism)