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J. Biol. Chem., Vol. 281, Issue 21, 14948-14960, May 26, 2006

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Deoxycholic Acid Induces Intracellular Signaling through Membrane Perturbations^*

Samira Jean-Louis, Sandeep Akare, M. Ahad Ali^¶, Eugene A. Mash, Jr.^¶, Emmanuelle Meuillet^||**, and Jesse D. Martinez¹

From the Cancer Biology Interdisciplinary Program, the ^¶Synthetic Chemistry Shared Service, the ^||Department of Nutritional Sciences, the ^**Department of Molecular and Cellular Biology, and the Department of Cellular Biology and Anatomy, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724

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--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.

Received for publication, June 20, 2005 , and in revised form, February 23, 2006.

^* This work was supported by National Institutes of Health Grant CA72008 and by Minority Supplement CA072008-08S1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cellular Biology and Anatomy, P. O. Box 245024, 1501 N. Campbell Ave., Tucson, AZ 85724. Tel.: 520-626-4250; Fax: 520-626-4480; E-mail: jmartinez{at}azcc.arizona.edu.

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