Bile acid biological activity in colon cancer cells: From hydrophobicity to gene activation
AuthorPowell, Ashley Ann
AdvisorMartinez, Jesse D.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractBile acids, known for millennia to play a role in health and disease, are currently being studied for their pivotal contribution to the development and possible prevention of colon cancer. Some bile acids have long been suspected to play a role in the development of colon cancer. Particularly, highly hydrophobic bile acids, such as deoxycholic acid (DCA), are known to promote the formation of colon tumors in animal models. However, one moderately hydrophobic bile acid, ursodeoxycholic acid (UDCA), has been shown to be a colon cancer chemopreventive agent, although its mechanism of action is unknown. Originally, it was believed that increased hydrophobicity caused high levels of cell membrane perturbation and digestion, thus resulting in cell death. In addition, it was believed that bile acids could cross membranes to a level related to their hydrophobicity and interact with intracellular molecules to induce biological responses. My studies have shown that while bile acid biological activity is related to hydrophobicity, bile acids do not have the innate ability to cross colon cell membranes. While highly hydrophobic bile acids cause a rapid induction of apoptosis and moderately hydrophobic bile acids cause growth arrest in colon cells, no evidence could be found to show that bile acids could enter colon cells. In fact, my data indicate that bile acids activate signaling cascades through transmembrane receptors on the plasma membrane. It is the activation of these signaling pathways, which result in DCA-induced apoptosis or UDCA-induced growth arrest. My studies have shown that DCA has the ability to activate GADDI53, FADD, and caspase 8 and that activation of these molecules is necessary to produce apoptosis. Additionally, I discovered that UDCA activates Rb and GADD153 and has the ability to induce GI growth arrest and protect cells from DCA induced apoptosis. Interestingly, I found that while DCA and UDCA cause drastically different cellular responses, my data suggest that they signal through shared pathways. I show that UDCA could abrogate DCA activity. These studies also show two possible by which UDCA acts as a chemo-preventive agent: by causing growth arrest and by preventing DCA-induced apoptosis.
Degree ProgramGraduate College