title: Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis.
abstract: Epidemiological evidence indicates that non-steroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) to a greater degree than other non-gastrointestinal cancers, but the molecular basis for this difference is unknown. We previously reported that aspirin induces signal-specific I kappa B alpha degradation followed by NF kappa B nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. Here, we explored the hypothesis that cell-type specific effects on NF kappa B signalling are responsible for the observed differences in protection by aspirin against CRC compared to breast and gynaecological cancers. We also assessed whether COX-2 expression, mutation status of adenomatous polyposis coli (APC), beta-catenin, p53, or DNA mismatch repair (MMR) genes in CRC lines influenced aspirin-induced effects. We found that aspirin induced concentration-dependent I kappa B alpha degradation, NF kappa B nuclear translocation and apoptosis in all CRC lines studied. However, there was no such effect on the other cancer cell types, indicating a considerable degree of cell-type specificity. The lack of effect on NF kappa B signalling, paralleled by absence of an apoptotic response to aspirin in non-CRC lines, strongly suggests a molecular rationale for the particular protective effect of NSAIDs against CRC. Effects on NF kappa B and apoptosis were observed irrespective of COX-2 expression, or mutation status in APC, beta-catenin, p53 and DNA MMR genes, underscoring the generality of the aspirin effect on NF kappa B in CRC cells. These findings raise the possibility of cell-type specific targets for the development of novel chemopreventive agents.
authors.affiliation: Colon Cancer Genetics Group, University of Edinburgh Department of Oncology and MRC Human Genetics Unit, Western General Hospital, Crewe Rd, Edinburgh EH4 2XU, Scotland.
authors.forename: F V N
authors.initials: FV
authors.lastname: Din
authors.forename: M G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: L A
authors.initials: LA
authors.lastname: Stark
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008565:Membrane Proteins; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D021381:Protein Transport; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003598:Cytoskeletal Proteins; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin