Co-inhibition of polo-like kinase 1 and Aurora kinases promotes mitotic catastrophe.

Jingjing Li,Randy Y.C Poon,Wing Yu Man,Hoi Tang Ma,Joyce P.Y Mak,Myung Jin Hong,Jeremy P.H Chow

doi:10.18632/oncotarget.3313

Jingjing Li, Randy Y.C Poon + Show 5 more

Open Access

https://doi.org/10.18632/oncotarget.3313

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Journal: Oncotarget	Publication Date: Mar 20, 2015
Citations: 26	License type: cc-by

Affiliation: Hong Kong University of Science and Technology

Abstract

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.

Highlights

Accurate cell division relies on the actions of a wellbalanced network of protein kinases and phosphatases [1]
After HeLa cells were transfected with siRNAs against AURKA and AURKB, they were synchronized at either G2 phase or mitosis
We provided several lines of evidence suggesting that combining inhibitors of PLK1 and Aurora kinases induced more mitotic defects than individual inhibitors alone

Summary

Introduction

Accurate cell division relies on the actions of a wellbalanced network of protein kinases and phosphatases [1]. Polo-like kinases and Aurora kinases are two of the most studied families of mitotic kinases These kinases performs multiple functions in mitosis, including centrosome maturation, kinetochore-spindle attachment, chromosome segregation, and cytokinesis. One of the critical functions of polo-like kinase 1(PLK1) in mitosis is for kick-starting the autocatalytic loop that controls the activity of cyclin B1–CDK1 [2]. In addition to regulating cyclin B1–CDK1 activity through the CDC25/WEE1 axis, PLK1 controls the localization of cyclin B1 by phosphorylating its nuclear export sequence. This inhibits the binding of the export receptor CRM1, thereby triggering nuclear accumulation and activation of cyclin B1 during prophase [8]

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