Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition

Sadaie, M., Dillon, C., Narita, M., Young, A.R.J., Cairney, C., Godwin, L.S., Torrance, C.J., Bennett, D.C., Keith, N. and Narita, M. (2015) Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition. Molecular Biology of the Cell, 26(17), pp. 2971-2985. (doi:10.1091/mbc.E15-01-0003) (PMID:26133385)

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Abstract

Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cairney, Dr Claire and Keith, Professor Nicol
Authors: Sadaie, M., Dillon, C., Narita, M., Young, A.R.J., Cairney, C., Godwin, L.S., Torrance, C.J., Bennett, D.C., Keith, N., and Narita, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Biology of the Cell
Publisher:American Society for Cell Biology
ISSN:1059-1524
ISSN (Online):1939-4586
Copyright Holders:Copyright © 2015 Sadaie et al.
First Published:First published in Molecular Biology of the Cell 26(17):2971-2985
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
415271Telomerase therapeuticsNicol KeithCancer Research UK (CAN-RES-UK)C301/A6691RI CANCER SCIENCES
476261In Vitro Modelling and Imaging in Oncology Drug DiscoveryNicol KeithCancer Research UK (CAN-RES-UK)C301/A9892RI CANCER SCIENCES