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

Abstract

Substantial evidence indicates that aspirin has antitumour activity against large bowel cancer and modulation of the NF-kappaB (NF-κB) signalling pathway has been identified as a key mechanism in this effect. However, studies examining how aspirin affects the NF-κB 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-κB 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 IkBa in xenografted HT-29 tumours and in adenomas from APCMin+/- mice. Furthermore, we show that this response occurs in a timedependent manner and is paralleled by nuclear translocation of p65 and caspase activation. Using high performance liquid chromatography analysis, we demonstrate that