Oncotarget

Research Papers: Chromosome:

Cenp-E inhibitor GSK923295: Novel synthetic route and use as a tool to generate aneuploidy

Ailsa Bennett _, Beatrice Bechi, Anthony Tighe, Sarah Thompson, David J Procter, Stephen S Taylor

PDF  |  HTML  |  Supplementary Files  |  Order a Reprint

Oncotarget. 2015; 6:20921-20932. https://doi.org/10.18632/oncotarget.4879

Metrics: PDF 1380 views  |   HTML 860 views  |   ?  


Abstract

Ailsa Bennett1, Beatrice Bechi2, Anthony Tighe1, Sarah Thompson1, David J. Procter2, Stephen S. Taylor1

1Faculty of Life Sciences, University of Manchester, United Kingdom

2School of Chemistry, University of Manchester, United Kingdom

Correspondence to:

Stephen S. Taylor, e-mail: stephen.taylor@manchester.ac.uk

Keywords: Chromosome Section, spindle assembly checkpoint, Mps1, aneuploidy, chromosome instability, Cenp-E

Received: July 02, 2015     Accepted: July 24, 2015     Published: August 06, 2015

ABSTRACT

Aneuploidy is a common feature of cancer, with human solid tumour cells typically harbouring abnormal chromosome complements. The aneuploidy observed in cancer is often caused by a chromosome instability phenotype, resulting in genomic heterogeneity. However, the role aneuploidy and chromosome instability play in tumour evolution and chemotherapy response remains poorly understood. In some contexts, aneuploidy has oncogenic effects, whereas in others it is anti-proliferative and tumour-suppressive. Dissecting fully the role aneuploidy plays in tumourigenesis requires tools and facile assays that allow chromosome missegregation to be induced experimentally in cells that are otherwise diploid and chromosomally stable. Here, we describe a chemical biology approach that induces low-level aneuploidy across a large population of cells. Specifically, cells are first exposed to GSK923295, an inhibitor targeting the mitotic kinesin Cenp-E; while the majority of chromosomes align at the cell's equator, a small number cluster near the spindle poles. By then driving these cells into anaphase using AZ3146, an inhibitor targeting the spindle checkpoint kinase Mps1, the polar chromosomes are missegregated. This results in, on average, two chromosome missegregation events per division, and avoids trapping chromosomes in the spindle midzone, which could otherwise lead to DNA damage. We also describe an efficient route for the synthesis of GSK923295 that employs a novel enzymatic resolution. Together, the approaches described here open up new opportunities for studying cellular responses to aneuploidy.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4879