A Novel Mechanism for Bile Acid Induced Activation of Estrogen Receptor β in Colorectal Cancer
PublisherThe University of Arizona.
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AbstractPrimary bile acids are a group of cholesterol metabolites that are synthesized in the liver and stored in the gallbladder. The main role of bile acids is to aid in the digestion of dietary fats and lipids. More recently, a signaling role for bile acids has been characterized. Secondary bile acids are formed when the bacteria of the colon metabolize primary bile acids. Secondary bile acids that escape enterohepatic re-uptake to the liver can have a deleterious effect in the colon. Deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) are two secondary bile acids that have been studied for their biological effects in the colon. More recently, these bile acids have been found to induce intracellular signaling in the colon. Although much is known about bile acids and their link to tumorigenesis or chemoprevention, there is very little known about how they induce the intracellular signaling of cells. In short, it is our goal to understand the mechanism of how bile acids like DCA and UDCA induce the activation of signaling pathways. For several years, bile acids have slowly been characterized as hormonal molecules due to their ability to naturally bind to the farnesoid x receptor (FXR) and pregnane x receptor (PXR). Moreover, DCA and UDCA have also been researched for their gender specific role. In animal models, UDCA was found to be a chemopreventive agent in males, but a tumor-promoting agent in females. In our studies, we identified a novel nuclear receptor that bile acids exert their effect on. Estrogen receptor β (ERβ) is highly predominant in the colon and a regulator of colorectal cancer. Using human colorectal adenocarcinoma cell lines, we identified a key serine residue (Serine-87) on ERβ that is highly regulated by the MAPK pathway. We found that DCA and UDCA induce the phosphorylation and subsequent up-regulation of estrogen receptor regulated genes. Moreover, we found that phosphorylation was occurring mainly in the nucleus of our cells, indicative of activation of ERβ. Remarkably, we also identified a tumorigenic role for UDCA. UDCA-treated cells showed increased migration, which was blocked when the MAPK and ERβ pathways were inhibited. Collectively, this data reveals a novel signaling mechanism for bile acids in colorectal cancer and uncovers an adverse role for UDCA.
Degree ProgramGraduate College