The role of the bile acid deoxycholate in gastrointestinal epithelial cell signalling

THESIS 7574Environmental and dietary factors are implicated in the aetiology of human cancer. Bile acids, the amphiphilic derivatives of cholesterol, are strongly implicated in colonic and oesophageal carcinogenesis. While bile acids themselves cannot induce tumours, they are generally regarded as being tumour promoters. The exact mechanism of their tumour promoting activity is uncertain but it is likely to involve alterations in epithelial cell signalling cascades and gene expression systems. The ability of deoxycholic acid (DCA), a potent bile acid, to modify intracellular signalling cascades such as protein kinase C (PKC) and mitogen activated protein kinase (MAPK) was examined. As bile acids are also thought to mediate their tumour promoting effects through transcriptional deregulation, DCAinduced alterations in the transcription factor, activator protein-1 (AP-1), were investigated. The findings of this thesis provide a further understanding of the role of DCA in gastrointestinal tumour cell development through the persistent activation of MAPK and AP-1 contributing to deregulated expression of downstream targets such as COX-2