Co-inhibition of polo-like kinase 1 and Aurora kinases promotes mitotic catastrophe
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Jingjing Li1, Myung Jin Hong1, Jeremy P.H. Chow1, Wing Yu Man1, Joyce P.Y. Mak1, Hoi Tang Ma1, Randy Y.C. Poon1
1Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
Randy Y.C. Poon, e-mail: firstname.lastname@example.org
Keywords: anticancer drugs, antimitotic drugs, kinases, mitosis, mitotic slippage
Received: November 04, 2014 Accepted: February 08, 2015 Published: March 20, 2015
Mitosis is choreographed by a number of protein kinases including polo-like kinases and Aurora kinases. As these kinases are frequently dysregulated in cancers, small-molecule inhibitors have been developed for targeted anticancer therapies. Given that PLK1 and Aurora kinases possess both unique functions as well as co-regulate multiple mitotic events, whether pharmacological inhibition of these kinases together can enhance mitotic catastrophe remains an outstanding issue to be determined. Using concentrations of inhibitors that did not induce severe mitotic defects on their own, we found that both the metaphase arrest and mitotic slippage induced by inhibitors targeting Aurora A and Aurora B (MK-5108 and Barasertib respectively) were enhanced by a PLK1 inhibitor (BI 2536). We found that PLK1 is overexpressed in cells from nasopharyngeal carcinoma, a highly invasive cancer with poor prognosis, in comparison to normal nasopharyngeal epithelial cells. Nasopharyngeal carcinoma cells were more sensitive to BI 2536 as a single agent and co-inhibition with Aurora kinases than normal cells. These observations underscore the mechanism and potential benefits of targeting PLK1 and Aurora kinases to induce mitotic catastrophe in cancer cells.
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