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BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling

Urban, Bettina C.; Collard, Tracey J.; Eagle, Catherine J.; Southern, Samantha L.; Greenhough, Alexander; Hamdollah-Zadeh, Maryam; Ghosh, Anil; Poulsom, Richard; Paraskeva, Christos; Silver, Andrew; Williams, Ann C.

BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling Thumbnail


Authors

Bettina C. Urban

Tracey J. Collard

Catherine J. Eagle

Samantha L. Southern

Maryam Hamdollah-Zadeh

Anil Ghosh

Richard Poulsom

Christos Paraskeva

Andrew Silver

Ann C. Williams



Abstract

Objective Colorectal cancer remains the fourth most common cause of cancer-related mortality worldwide. Here we investigate the role of nuclear factor-?B (NF-?B) co-factor B-cell CLL/lymphoma 3 (BCL-3) in promoting colorectal tumour cell survival. Design Immunohistochemistry was carried out on 47 tumour samples and normal tissue from resection margins. The role of BCL-3/NF-?B complexes on cell growth was studied in vivo and in vitro using an siRNA approach and exogenous BCL-3 expression in colorectal adenoma and carcinoma cells. The question whether BCL-3 activated the AKT/protein kinase B (PKB) pathway in colorectal tumour cells was addressed by western blotting and confocal microscopy, and the ability of 5- aminosalicylic acid (5-ASA) to suppress BCL-3 expression was also investigated. Results We report increased BCL-3 expression in human colorectal cancers and demonstrate that BCL-3 expression promotes tumour cell survival in vitro and tumour growth in mouse xenografts in vivo, dependent on interaction with NF-?B p50 or p52 homodimers. We show that BCL-3 promotes cell survival under conditions relevant to the tumour microenvironment, protecting both colorectal adenoma and carcinoma cells from apoptosis via activation of the AKT survival pathway: AKT activation is mediated via both PI3K and mammalian target of rapamycin (mTOR) pathways, leading to phosphorylation of downstream targets GSK- 3 and FoxO1/3a. Treatment with 5-ASA suppressed BCL-3 expression in colorectal cancer cells. Conclusions Our study helps to unravel the mechanism by which BCL-3 is linked to poor prognosis in colorectal cancer; we suggest that targeting BCL-3 activity represents an exciting therapeutic opportunity potentially increasing the sensitivity of tumour cells to conventional therapy.

Citation

Urban, B. C., Collard, T. J., Eagle, C. J., Southern, S. L., Greenhough, A., Hamdollah-Zadeh, M., …Williams, A. C. (2016). BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling. Gut, 65(7), 1151-1164. https://doi.org/10.1136/gutjnl-2014-308270

Journal Article Type Article
Acceptance Date Mar 21, 2015
Online Publication Date Jun 1, 2015
Publication Date Jul 1, 2016
Deposit Date Feb 12, 2019
Publicly Available Date Mar 28, 2024
Journal Gut
Print ISSN 0017-5749
Electronic ISSN 1468-3288
Publisher BMJ Publishing Group
Peer Reviewed Peer Reviewed
Volume 65
Issue 7
Pages 1151-1164
DOI https://doi.org/10.1136/gutjnl-2014-308270
Public URL https://uwe-repository.worktribe.com/output/910367
Publisher URL https://doi.org/10.1136/gutjnl-2014-308270