Aspirin activates the NF-kappaB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer.
Substantial evidence indicates that aspirin has antitumour activity against large bowel cancer and modulation of the NF-kappaB (NF-kappaB) signalling pathway has been identified as a key mechanism in this effect. However, studies examining how aspirin affects the NF-kappaB 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-kappaB 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 IkappaBalpha in xenografted HT-29 tumours and in adenomas from APC(Min+/-) 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 high performance liquid chromatography analysis, we demonstrate that >0.5 mM salicylate levels are achievable in xenografted tumours after low-dose aspirin (40 mg/kg) treatment and that these levels, which are pharmacologically relevant to humans, are sufficient to stimulate an NF-kappaB and apoptotic response. We demonstrate that activation of the NF-kappaB 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 APC(Min+/-) mice. These in vivo findings further establish that aspirin induces activation of the NF-kappaB pathway in neoplastic epithelial cells and provide further support that this effect is important for the antitumour activity of the agent. These data have considerable relevance to cancer prevention and therapy.
Stark
Lesley A
LA
Division of Oncology, School of Clinical and Molecular Medicine, University of Edinburgh, Colon Cancer Genetics Group, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. lesley.stark@hgu.mrc.ac.uk
Reid
Kirsten
K
Sansom
Owen J
OJ
Din
Farhat V
FV
Guichard
Sylvie
S
Mayer
Iain
I
Jodrell
Duncan I
DI
Clarke
Alan R
AR
Dunlop
Malcolm G
MG
D000818:Animals; D017209:Apoptosis; D001241:Aspirin / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011230:Precancerous Conditions / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D016328:NF-kappa B; D001241:Aspirin