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

Linda Smith; Raed Farzan; Simak Ali; Laki Buluwela; Adrian Saurin; David W. Meek

doi:10.1038/s41598-017-16394-2

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

Linda Smith
, Raed Farzan
, Simak Ali
, Laki Buluwela
, Adrian Saurin
, David W. Meek (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

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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.

Original language	English
Article number	16115
Pages (from-to)	1-12
Number of pages	12
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-16394-2
Publication status	Published - 23 Nov 2017

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cancer therapeutic resistance
Tumour-suppressor proteins

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Author Correction: The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation (Scientific Reports (2017) DOI: 10.1038/s41598-017-16394-2)
Smith, L., Farzan, R., Ali, S., Buluwela, L., Saurin, A. T. & Meek, D. W. (Lead / Corresponding author), 22 Mar 2018, In: Scientific Reports. 8, 1 p., 5237.
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title = "The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation",

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.",

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author = "Linda Smith and Raed Farzan and Simak Ali and Laki Buluwela and Adrian Saurin and Meek, \{David W.\}",

note = "This work was supported by the Medical Research Council (UK) Integrative Toxicology Training Partnership; Cancer Research UK Programme Foundation Award C47320/A21229); and Cancer Research UK grant number C37/A18784. RF is supported by a PhD scholarship from King Saud University, Riyadh, Kingdom of Saudi Arabia.",

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N1 - This work was supported by the Medical Research Council (UK) Integrative Toxicology Training Partnership; Cancer Research UK Programme Foundation Award C47320/A21229); and Cancer Research UK grant number C37/A18784. RF is supported by a PhD scholarship from King Saud University, Riyadh, Kingdom of Saudi Arabia.

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AB - 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.

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

Abstract

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Author Correction: The responses of cancer cells to PLK1 inhibitors reveal a novel protective role for p53 in maintaining centrosome separation (Scientific Reports (2017) DOI: 10.1038/s41598-017-16394-2)

Cite this