Deoxycholic acid induces intracellular signaling through membrane perturbations.
Secondary bile acids have long been postulated to be tumor promoters in the colon; however, their mechanism of action remains unclear. In this study, we examined the actions of bile acids at the cell membrane and found that they can perturb membrane structure by alteration of membrane microdomains. Depletion of membrane cholesterol by treating with methyl-beta-cyclodextrin suppressed deoxycholic acid (DCA)-induced apoptosis, and staining for cholesterol with filipin showed that DCA caused a marked rearrangement of this lipid in the membrane. Likewise, DCA was found to affect membrane distribution of caveolin-1, a marker protein that is enriched in caveolae membrane microdomains. Additionally, fluorescence anisotropy revealed that DCA causes a decrease in membrane fluidity consistent with the increase in membrane cholesterol content observed after 4 h of DCA treatment of HCT116 cells. Significantly, by using radiolabeled bile acids, we found that bile acids are able to interact with and localize to microdomains differently depending on their physicochemical properties. DCA was also found to induce tyrosine phosphorylation and activate the receptor tyrosine kinase epidermal growth factor receptor in a ligand-independent manner. In contrast, ursodeoxycholic acid did not exhibit any of these effects even though it interacted significantly with the microdomains. Collectively, these data suggest that bile acid-induced signaling is initiated through alterations of the plasma membrane structure and the redistribution of cholesterol.
Cancer Biology Interdisciplinary Program, Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
Samira
S
Jean-Louis
Sandeep
S
Akare
M Ahad
MA
Ali
Eugene A
EA
Mash
Emmanuelle
E
Meuillet
Jesse D
JD
Martinez
D017209:Apoptosis; D001647:Bile Acids and Salts / Q000737:chemistry; D051242:Caveolin 1 / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002518:Ceramides / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism; D003840:Deoxycholic Acid / Q000737:chemistry*; D003902:Detergents / Q000494:pharmacology; D006801:Humans; D008055:Lipids / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014580:Ursodeoxycholic Acid / Q000737:chemistry
D001647:Bile Acids and Salts; D051242:Caveolin 1; D002518:Ceramides; D003902:Detergents; D008055:Lipids; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D002784:Cholesterol