Skip Navigation



Carcinogenesis Advance Access published online on November 28, 2006
Carcinogenesis, doi:10.1093/carcin/bgl220
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
28/5/968    most recent
bgl220v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Stark, L. A.
Right arrow Articles by Dunlop, M. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stark, L. A.
Right arrow Articles by Dunlop, M. G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 16, 2006
Revised October 6, 2006
Accepted November 3, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Aspirin activates the NF-{kappa}B signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer

Lesley A. Stark 1 *, Kirsten Reid 1, Owen J Sansom 2, Farhat V Din 1, Sylvie Guichard 3, Iain Mayer 3, Duncan I Jodrell 3, Alan R Clarke 4, and Malcolm G. Dunlop 1

1 Colon Cancer Genetics Group, University of Edinburgh Division of Oncology, School of Clinical and Molecular Medicine and MRC Human Genetics Unit, Western General Hospital, Crewe Rd., Edinburgh, Scotland EH4 2XU
2 Beatson Institute for Cancer Research, Garscube Estate, Glasgow. Cancer Research UK
3 Cancer Research UK Pharmacology and Drug Development Group, University of Edinburgh Cancer Research Centre, Edinburgh, EH4 2XR
4 Cardiff School of Biosciences, Cardiff University, Cardiff CF103US

* To whom correspondence should be addressed.
Lesley A. Stark, E-mail: Lesley.Stark{at}hgu.mrc.ac.uk


  Abstract

Substantial evidence indicates that aspirin has anti-tumour activity against large bowel cancer and modulation of the NF-{kappa}B signalling pathway has been identified as a key mechanism in this effect. However, studies examining how aspirin affects the NF-{kappa}B pathway to promote apoptosis have been restricted to in vitro analysis in tissue culture systems and have produced contrasting results. Here, we employed two animal models of human colorectal cancer to determine aspirin effects on the NF-{kappa}B pathway in colorectal neoplasia in vivo, and the relationship of such effects to the induction of apoptosis. We demonstrate that aspirin induces phosphorylation and degradation of cytoplasmic I{kappa}B{alpha} in xenografted HT-29 tumours and in adenomas from APCMin+/- mice. Furthermore, we show that this response occurs in a time dependent manner and is paralleled by nuclear translocation of p65 and caspase activation. Using HPLC analysis, we demonstrate that >0.5mM salicylate levels are achievable in xenografted tumours after low dose aspirin (40mg/kg) treatment and that these levels, which are pharmacologically relevant to humans, are sufficient to stimulate an NF-{kappa}B and apoptotic response. We demonstrate that activation of the NF-{kappa}B pathway is associated with increased apoptosis in neoplastic epithelial cells, but found that aspirin has a minimal effect on nuclear p65 and apoptosis in normal intestinal mucosa from APCMin+/- mice. These in vivo findings further establish that aspirin induces activation of the NF-{kappa}B pathway in neoplastic epithelial cells and provide further support that this effect is important for the anti-tumour activity of the agent. These data have considerable relevance to cancer prevention and therapy.

Keywords: NF-kappaB; aspirin; xenograft; APCMin colon cancer; mouse model.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.