The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation

Linda Smith,Raed Farzan,Laki Buluwela,Adrian T Saurin,David W Meek,Simak Ali

doi:10.1038/s41598-017-16394-2

Linda Smith, Raed Farzan + Show 4 more

Open Access

https://doi.org/10.1038/s41598-017-16394-2

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Abstract

Polo-like kinase-1 (PLK1) plays a major role in driving mitotic events, including centrosome disjunction and separation, and is frequently over-expressed in human cancers. PLK1 inhibition is a promising therapeutic strategy and works by arresting cells in mitosis due to monopolar spindles. The p53 tumour suppressor protein is a short-lived transcription factor that can inhibit the growth, or stimulate the death, of developing cancer cells. Curiously, although p53 normally acts in an anti-cancer capacity, it can offer significant protection against inhibitors of PLK1, but the events underpinning this effect are not known. Here, we show that functional p53 reduces the sensitivity to PLK1 inhibitors by permitting centrosome separation to occur, allowing cells to traverse mitosis and re-enter cycle with a normal complement of 2N chromosomes. Protection entails the activation of p53 through the DNA damage-response enzymes, ATM and ATR, and requires the phosphorylation of p53 at the key regulatory site, Ser15. These data highlight a previously unrecognised link between p53, PLK1 and centrosome separation that has therapeutic implications for the use of PLK1 inhibitors in the clinic.

Highlights

Polo-like kinase-1 (PLK1) plays a major role in driving mitotic events, including centrosome disjunction and separation, and is frequently over-expressed in human cancers
Underpinning this effect, we find that the early mitotic delay induced by PLK1 inhibitors is significantly less in cells expressing wild type p53 which, unlike p53-null cells, are able to maintain the integrity of centrosome movement
We confirm that p53 can offer a selective advantage to cancer cells treated with PLK1 inhibitors

Summary

Introduction

Polo-like kinase-1 (PLK1) plays a major role in driving mitotic events, including centrosome disjunction and separation, and is frequently over-expressed in human cancers. Protection entails the activation of p53 through the DNA damageresponse enzymes, ATM and ATR, and requires the phosphorylation of p53 at the key regulatory site, Ser[15] These data highlight a previously unrecognised link between p53, PLK1 and centrosome separation that has therapeutic implications for the use of PLK1 inhibitors in the clinic. PLK1 is a member of the polo-like kinase (PLK) family that mediates several key functions throughout mitosis including centrosome disjunction and movement, activation of cyclin B/CDK1, spindle assembly, and cytokinesis[15,16]. Consistent with these roles, inhibition of PLK1 arrests cells in early mitosis with a characteristic polo “ring” of chromosomes undergoing monopolar attachment to duplicated but unseparated centrosomes. PLK1 expression is down-regulated by p53 as part of the G2/M checkpoint[24,25,26] and its levels are elevated in a range of different tumour types, especially where p53 function has been lost[27]

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