Mitotic entry: Non-genetic heterogeneity exposes the requirement for Plk1

Abstract

// Claire F. Aspinall 1 , Daniella Zheleva 2 , Anthony Tighe 1 , Stephen S. Taylor 1 1 Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom 2 Cyclacel Ltd, Dundee DD1 5JJ, United Kingdom Correspondence to: Stephen S. Taylor, e-mail: stephen.taylor@manchester.ac.uk Keywords: mitosis, Plk1 Received: August 31, 2014      Accepted: September 30, 2015      Published: October 13, 2015 ABSTRACT The quest to develop novel antimitotic chemotherapy agents has led to the generation of several small molecule inhibitors targeting Plk1, a protein kinase required for multiple aspects of cell division. Previous studies have shown that upon exposure to Plk1 inhibitors, cells enter mitosis, delay briefly in prophase and then arrest in mitosis due to an inability to undergo centrosome separation. Here, we show that four different classes of Plk1 inhibitor block mitotic entry in several cancer cell lines and non-transformed RPE-1 cells. The proportion of cells that arrest in G2 is cell line and concentration dependent, and is subject to non-genetic heterogeneity. Following inhibitor washout, the G2 block is alleviated and cells enter mitosis but then fail to complete cell division indicating that most Plk1 inhibitors are not fully reversible. An exception is CYC140844; in contrast to five other inhibitors examined here, this novel Plk1 inhibitor is fully reversible. We discuss the implications for developing Plk1 inhibitors as chemotherapy agents and research tools.