Membrane Perturbation By Bile Acids and Their Potential Role in Signaling

Abstract

Secondary bile acids have long been postulated to be tumor promoters in the colon but their mechanism of action are yet to be delineated. Though most bile acids are chemically similar, they have been found to exert contrasting signaling effects in the colonic epithelium. Particularly, hydrophobic bile acids such as deoxycholic acid (DCA) are found to be tumor promoters while their hydrophilic counterparts such as ursodeoxycholic acid (UDCA) are chemopreventive. Given the fact that colon cells do not possess bile acid transporters, the question that arises is how do bile acids activate intracellular signaling? In our studies, we examined the actions of bile acids at the cell membrane and found that hydrophobic bile acids can perturb membrane structure. This membrane perturbation was found to be characterized by a change in membrane fluidity and by cholesterol aggregation. Additionally, several membrane associated proteins were found to be deregulated in response to DCA further supporting the above conclusion regarding membrane perturbation. Moreover, caveolin, a negative regulator of membrane microdomains was seen to be dephosphorylated and disassociated from the membrane microdomains, implicating membrane microdomains as a possible target of the effects of DCA on the membrane. Consistent with this, we found that DCA was able to cause rapid and sustained activation of the receptor tyrosine kinase, EGFR and that this activation was ligand-independent. Using fluorescent-tagged bile acids we showed increased aggregation and clustering in the membranes treated with FITC-DCA in a manner that was reminiscent of receptor activation in immune cells. Collectively, these data suggest that bile-acid induced signaling is likely to be initiated through alterations of the plasma membrane structure in colon cancer cells.