Journal Article

BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-κB activity

Nadine K. Clemo, Tracey J. Collard, Samantha L. Southern, Kieron D. Edwards, Moganaden Moorghen, Graham Packham, Angela Hague, Christos Paraskeva and Ann C. Williams

in Carcinogenesis

Volume 29, issue 4, pages 849-857
Published in print April 2008 | ISSN: 0143-3334
Published online January 2008 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgn004
BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-κB activity

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Although expression of the anti-apoptotic protein Bcl-2-associated athanogene-1 (BAG-1) has been reported as up-regulated in a number of malignancies, we show for the first time that BAG-1 is over-expressed in medium/large-sized colorectal adenomas and carcinomas compared with normal epithelium. To investigate whether expression of BAG-1 is important for colorectal tumour cell survival, microarray analysis was carried out on the HCT116 colorectal carcinoma cell line following transfection with BAG-1 small interfering RNA (siRNA). Analysis identified altered expression of a subset of potential nuclear factor-κB (NF-κB)-regulated genes. Furthermore, knock down of BAG-1 was shown to inhibit NF-κB transcriptional activity. Inhibition of NF-κB activity using BAG-1 siRNA or the NF-κB inhibitor BAY-117082 suppressed HCT116 cell yield and induced apoptosis; combined treatment had no additive effect, suggesting that the decrease in cell yield associated with knock down of BAG-1 expression is mediated via inhibition of NF-κB. Of clinical relevance, BAG-1 siRNA sensitized colorectal carcinoma cells to apoptosis induced by potential therapeutic agent TRAIL as well as tumour necrosis factor-α, both inducers of NF-κB activity. In summary, knock down of BAG-1 leads to inhibition of NF-κB, identifying BAG-1 as a novel regulator of NF-κB. It is proposed that, by inhibiting NF-κB, suppression of BAG-1 could represent a novel strategy to impede colorectal cancer cell survival and as an adjuvant increase sensitivity to current therapeutic regimes.

Journal Article.  6888 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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