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


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Authors

Sadaie, Mahito 
Dillon, Christian 
Young, Andrew RJ 
Cairney, Claire J 

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.

Description

Keywords

Aurora Kinase B, Cell Division, Cell Line, Cell Nucleus, Cellular Senescence, Chromosome Segregation, Cytokinesis, HeLa Cells, High-Throughput Screening Assays, Humans, Mitosis, Phenotype, Polyploidy, Protein Kinase Inhibitors, Small Molecule Libraries

Journal Title

Mol Biol Cell

Conference Name

Journal ISSN

1059-1524
1939-4586

Volume Title

26

Publisher

American Society for Cell Biology (ASCB)
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (15890)
This work was supported by the University of Cambridge, Cancer Research UK, Hutchison Whampoa; Cancer Research UK grants A6691 and A9892 (M.N., N.K., C.J.T., D.C.B., C.J.C., L.S.G, and M.S.); a fellowship from the Uehara Memorial Foundation (M.S.).