BCL-3 loss sensitises colorectal cancer cells to DNA damage by targeting homologous recombination.

Autor: Parker C; Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University Walk, University of Bristol, Bristol BS8 1TD, UK., Chambers AC; Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University Walk, University of Bristol, Bristol BS8 1TD, UK. Electronic address: adam.chambers@bristol.ac.uk., Flanagan DJ; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD UK; Biomedicine Discovery Institute, Monash University, Melbourne 3800, Australia., Ho JWY; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD UK., Collard TJ; Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University Walk, University of Bristol, Bristol BS8 1TD, UK., Ngo G; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN UK., Baird DM; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN UK., Timms P; Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University Walk, University of Bristol, Bristol BS8 1TD, UK., Morgan RG; School of Life Sciences, University of Sussex, Sussex House, Falmer, Brighton BN1 9RH UK., Sansom OJ; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD UK., Williams AC; Colorectal Tumour Biology Group, School of Cellular and Molecular Medicine, Faculty of Life Sciences, Biomedical Sciences Building, University Walk, University of Bristol, Bristol BS8 1TD, UK. Electronic address: Ann.C.Williams@bristol.ac.uk.
Jazyk: angličtina
Zdroj: DNA repair [DNA Repair (Amst)] 2022 Jul; Vol. 115, pp. 103331. Date of Electronic Publication: 2022 Apr 16.
DOI: 10.1016/j.dnarep.2022.103331
Abstrakt: The proto-oncogene BCL-3 is upregulated in a subset of colorectal cancers (CRC), where it has been shown to enhance tumour cell survival. However, although increased expression correlates with poor patient prognosis, the role of BCL-3 in determining therapeutic response remains largely unknown. In this study, we use combined approaches in multiple cell lines and pre-clinical mouse models to investigate the function of BCL-3 in the DNA damage response. We show that suppression of BCL-3 increases γH2AX foci formation and decreases homologous recombination in CRC cells, resulting in reduced RAD51 foci number and increased sensitivity to PARP inhibition. Importantly, a similar phenotype is seen in Bcl3 -/- mice, where Bcl3 -/- mouse crypts also exhibit sensitivity to DNA damage with increased γH2AX foci compared to wild type mice. Additionally, Apc.Kras-mutant x Bcl3 -/- mice are more sensitive to cisplatin chemotherapy compared to wild type mice. Taken together, our results identify BCL-3 as a regulator of the cellular response to DNA damage and suggests that elevated BCL-3 expression, as observed in CRC, could increase resistance of tumour cells to DNA damaging agents including radiotherapy. These findings offer a rationale for targeting BCL-3 in CRC as an adjunct to conventional therapies and suggest that BCL-3 expression in tumours could be a useful biomarker in stratification of rectal cancer patients for neo-adjuvant chemoradiotherapy.
(Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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