Aneuploidy is a common feature of tumours that arise by errors in chromosome segregation during mitosis. The aim of this study was to evaluate possible signaling pathways involved in sensitization to
chemotherapy in cells with
chromosomal instability. We designed a screen using the fission yeast Squizossaccharomyces pombe, to isolate strains showing a phenotype of chromosome mis-segregation and higher sensitivity to the antitumoral
drug Bleomycin. We examined differences in gene expression using a comparative analysis of genome-wide expression of the wild type strain and one of the mutants. The results revealed a set of genes involved in cell cycle control, including Mad3/BubR1 and Chk1. We then studied the levels of these two
proteins in
colorectal cancer human cell lines with different genomic content. Among these, SW620 cells showed higher BubR1 and Chk1
mRNA levels than control cells under normal conditions. Since Chk1 is required for both S and G2/M checkpoints, and the microtubule-destabilizing agent,
nocodazole induces mitotic arrest, we attempted to investigate the potential anticancer effects of
nocodazole in combination with
cisplatin. These studies showed that SW620 cells undergo synergistic cell death after spindle checkpoint activation followed by
cisplatin treatment, suggesting a role of Chk1 in this checkpoint, very likely dependent on BubR1
protein. Importantly, Chk1-depleted SW620 cells lost this synergistic effect. In summary, we propose that Chk1 could be a
biomarker predictive of the efficacy of
chemotherapy across different types of
tumors with
aneuploidy. These findings may be potentially very useful for the stratification of patients for treatment.