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

BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-kappa B activity
BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-kappa B activity
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-kappa B (NF-kappa B)-regulated genes. Furthermore, knock down of BAG-1 was shown to inhibit NF-kappa B transcriptional activity. Inhibition of NF-kappa B activity using BAG-1 siRNA or the NF-kappa 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-kappa 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-alpha, both inducers of NF-kappa B activity. In summary, knock down of BAG-1 leads to inhibition of NF-kappa B, identifying BAG-1 as a novel regulator of NF-kappa B. It is proposed that, by inhibiting NF-kappa 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.
cancer, nf-kappa b, apoptosis, nuclear factor kappa b, growth, transcription, treatment, cyclin d1, colorectal-cancer, breast-cancer, survival, alternative translation initiation, gene, time, sirna, cells, induced apoptosis, genes, expression, carcinoma cells, protein, cell, epithelial-cells, inhibitor, malignancies, carcinoma, colorectal cancer, malignancy, transcriptional activity, bag-1, necrosis
0143-3334
849-857
Clemo, Nadine K.
839c60f3-3975-417d-bf9a-c59d7d41671a
Collard, Tracey J.
fa7fb6aa-efbe-4dc2-b978-92dbd8c96025
Southern, Samantha L.
2a061c98-f66c-4104-b4e6-e59677a1e619
Edwards, Kieron D.
f6188e02-ec97-4afb-99db-e309978e7807
Moorghen, Moganaden
323d9857-c07d-4bab-981d-0337fab9c4a7
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Hague, Angela
0e1199e4-08c3-4e8b-b40f-2fc61555e6f4
Paraskeva, Christos
a24d42af-bb82-4fc2-b30e-fdaa5b63199b
Williams, Ann C.
754a6874-3c07-4c28-b7c5-d3bafab6fdb5
Clemo, Nadine K.
839c60f3-3975-417d-bf9a-c59d7d41671a
Collard, Tracey J.
fa7fb6aa-efbe-4dc2-b978-92dbd8c96025
Southern, Samantha L.
2a061c98-f66c-4104-b4e6-e59677a1e619
Edwards, Kieron D.
f6188e02-ec97-4afb-99db-e309978e7807
Moorghen, Moganaden
323d9857-c07d-4bab-981d-0337fab9c4a7
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Hague, Angela
0e1199e4-08c3-4e8b-b40f-2fc61555e6f4
Paraskeva, Christos
a24d42af-bb82-4fc2-b30e-fdaa5b63199b
Williams, Ann C.
754a6874-3c07-4c28-b7c5-d3bafab6fdb5

Clemo, Nadine K., Collard, Tracey J., Southern, Samantha L., Edwards, Kieron D., Moorghen, Moganaden, Packham, Graham, Hague, Angela, Paraskeva, Christos and Williams, Ann C. (2008) BAG-1 is up-regulated in colorectal tumour progression and promotes colorectal tumour cell survival through increased NF-kappa B activity. Carcinogenesis, 29 (4), 849-857. (doi:10.1093/carcin/bgn004).

Record type: Article

Abstract

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-kappa B (NF-kappa B)-regulated genes. Furthermore, knock down of BAG-1 was shown to inhibit NF-kappa B transcriptional activity. Inhibition of NF-kappa B activity using BAG-1 siRNA or the NF-kappa 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-kappa 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-alpha, both inducers of NF-kappa B activity. In summary, knock down of BAG-1 leads to inhibition of NF-kappa B, identifying BAG-1 as a novel regulator of NF-kappa B. It is proposed that, by inhibiting NF-kappa 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.

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More information

Published date: 2008
Keywords: cancer, nf-kappa b, apoptosis, nuclear factor kappa b, growth, transcription, treatment, cyclin d1, colorectal-cancer, breast-cancer, survival, alternative translation initiation, gene, time, sirna, cells, induced apoptosis, genes, expression, carcinoma cells, protein, cell, epithelial-cells, inhibitor, malignancies, carcinoma, colorectal cancer, malignancy, transcriptional activity, bag-1, necrosis

Identifiers

Local EPrints ID: 62708
URI: https://eprints.soton.ac.uk/id/eprint/62708
ISSN: 0143-3334
PURE UUID: 1a62d7e9-a005-46d0-8c83-832b3c43b2a7
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691

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Date deposited: 11 Sep 2008
Last modified: 20 Jul 2019 01:08

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Contributors

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

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