Carcinogenesis Advance Access originally published online on January 19, 2008
Carcinogenesis 2008 29(4):849-857; doi:10.1093/carcin/bgn004
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BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-
B activity
Cancer Research UK Colorectal Tumour Biology Research Group, Department of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
1 Institute of Molecular Plant Sciences, University of Edinburgh EH9 3JH, Edinburgh, UK
2 Department of Pathology and Histology, Bristol Royal Infirmary, Bristol BS2 8HW, UK
3 Cancer Sciences Division, Cancer Research UK Clinical Centre, University of Southampton SO16 6YD, UK
4 Department of Oral and Dental Science, University of Bristol, Bristol BS1 2LY, UK
* To whom correspondence should be addressed. Tel: 0117 3312070; Fax: 0117 9287896;Email: Ann.C.Williams{at}bristol.ac.uk
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-
B (NF-B)-regulated genes. Furthermore, knock down of BAG-1 was shown to inhibit NF-B transcriptional activity. Inhibition of NF-B activity using BAG-1 siRNA or the NF-B 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-B. Of clinical relevance, BAG-1 siRNA sensitized colorectal carcinoma cells to apoptosis induced by potential therapeutic agent TRAIL as well as tumour necrosis factor-
, both inducers of NF-B activity. In summary, knock down of BAG-1 leads to inhibition of NF-B, identifying BAG-1 as a novel regulator of NF-B. It is proposed that, by inhibiting NF-B, 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.
Abbreviations: BAG-1, Bcl-2-associated athanogene-1; FBS, fetal bovine serum; NEG, negative; NF-B, nuclear factor-B; Q-PCR, quantitative polymerase chain reaction; siRNA, small interfering RNA; TNF, tumour necrosis factor
Received October 10, 2007; revised December 17, 2007; accepted December 27, 2007.