¹Colon Cancer Genetics Group, Department of Oncology, Division of Clinical and Molecular Medicine and MRC Human Genetics Unit, Western General Hospital, University of Edinburgh, Crewe Rd, Edinburgh EH4 2XU, Scotland

Correspondence: Professor MG Dunlop, E-mail: Malcolm.Dunlop@hgu.mrc.ac.uk

Revised 17 January 2005; Accepted 19 January 2005; Published online 15 March 2005.

Abstract

Substantial evidence indicates nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC). However, the molecular basis for this anti-tumour activity has not been fully elucidated. We previously reported that aspirin induces signal-specific IB degradation followed by NFB nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. We have also reported the relative specificity of this aspirin-induced NFB-dependent apoptotic effect for CRC cells, in comparison to other cancer cell types. It is now important to establish whether there is heterogeneity within CRC, with respect to the effects of aspirin on the NFB pathway and apoptosis. p53 signalling and DNA mismatch repair (MMR) are known to be deranged in CRC and have been reported as potential molecular targets for the anti-tumour activity of NSAIDs. Furthermore, both p53 and MMR dysfunction have been shown to confer resistance to chemotherapeutic agents. Here, we set out to determine the p53 and hMLH1 dependency of the effects of aspirin on NFB signalling and apoptosis in CRC. We specifically compared the effects of aspirin treatment on cell viability, apoptosis and NFB signalling in an HCT-116 CRC cell line with the p53 gene homozygously disrupted (HCT-116^p53-/-) and an HCT-116 cell line rendered MMR proficient by chromosomal transfer (HCT-116^+ch3), to the parental HCT-116 CRC cell line. We found that aspirin treatment induced apoptosis following IB degradation, NFB nuclear translocation and repression of NFB-driven transcription, irrespective of p53 and DNA MMR status. These findings are relevant for design of both novel chemopreventative agents and chemoprevention trials in CRC.