CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner

Prevo, R., Pirovano, G., Puliyadi, R., Herbert, K. J. , Rodriguez-Berriguete, G., O’Docherty, A., Greaves, W., McKenna, W. G. and Higgins, G. S. (2018) CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner. Cell Cycle, 17(12), pp. 1513-1523. (doi: 10.1080/15384101.2018.1491236) (PMID:30045664) (PMCID:PMC6132956)

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Abstract

Cyclin-dependent kinase 1 (CDK1) orchestrates the transition from the G2 phase into mitosis and as cancer cells often display enhanced CDK1 activity, it has been proposed as a tumor specific anti-cancer target. Here we show that the effects of CDK1 inhibition are not restricted to tumor cells but can also reduce viability in non-cancer cells and sensitize them to radiation in a cell cycle dependent manner. Radiosensitization by the specific CDK1 inhibitor, RO-3306, was determined by colony formation assays in three tumor lines (HeLa, T24, SQ20B) and three non-cancer lines (HFL1, MRC-5, RPE). Initial results showed that CDK1 inhibition radiosensitized tumor cells, but did not sensitize normal fibroblasts and epithelial cells in colony formation assays despite effective inhibition of CDK1 signaling. Further investigation showed that normal cells were less sensitive to CDK1 inhibition because they remained predominantly in G1 for a prolonged period when plated in colony formation assays. In contrast, inhibiting CDK1 a day after plating, when the cells were going through G2/M phase, reduced their clonogenic survival both with and without radiation. Our finding that inhibition of CDK1 can damage normal cells in a cell cycle dependent manner indicates that targeting CDK1 in cancer patients may lead to toxicity in normal proliferating cells. Furthermore, our finding that cell cycle progression becomes easily stalled in non-cancer cells under normal culture conditions has general implications for testing anti-cancer agents in these cells.

Item Type:Articles
Additional Information:G.S. Higgins is supported by a Cancer Research UK Clinician Scientist Award (Grant numbers C34326/A13092 and C34326/A19590). Additional support was provided by grants from Cancer Research UK and the Medical Research Council.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Herbert, Dr Katharine
Authors: Prevo, R., Pirovano, G., Puliyadi, R., Herbert, K. J., Rodriguez-Berriguete, G., O’Docherty, A., Greaves, W., McKenna, W. G., and Higgins, G. S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Cycle
Publisher:Taylor and Francis
ISSN:1538-4101
ISSN (Online):1551-4005
Published Online:25 July 2018
Copyright Holders:Copyright © 2018 Informa UK Limited, trading as Taylor and Francis Group
First Published:First published in Cell Cycle 17(12): 1513-1523
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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