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J. Biol. Chem., Vol. 282, Issue 17, 13098-13113, April 27, 2007

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Opposing Actions of Endocannabinoids on Cholangiocarcinoma Growth

RECRUITMENT OF Fas AND Fas LIGAND TO LIPID RAFTS^*

Sharon DeMorrow, Shannon Glaser, Heather Francis, Julie Venter, Bradley Vaculin, Shelley Vaculin^¶, and Gianfranco Alpini^¶||1

From the ^¶Central Texas Veterans Health Care System and the Departments of Medicine and ^||Systems Biology and Translational Medicine and Division of Research and Education, Scott and White Hospital and Texas A&M University System Health Science Center College of Medicine, Temple, Texas 76504

Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options. Modulation of the endocannabinoid system is being targeted to develop possible therapeutic strategies for a number of cancers; therefore, we evaluated the effects of the two major endocannabinoids, anandamide and 2-arachidonylglycerol, on numerous cholangiocarcinoma cell lines. Although anandamide was antiproliferative and proapoptotic, 2-arachidonylglycerol stimulated cholangiocarcinoma cell growth. Specific inhibitors for each of the cannabinoid receptors did not prevent either of these effects nor did pretreatment with pertussis toxin, a G_i/o protein inhibitor, suggesting that anandamide and 2-arachidonylglycerol did not exert their diametric effects through any known cannabinoid receptor or through any other G_i/o protein-coupled receptor. Using the lipid raft disruptors methyl--cyclodextrin and filipin, we demonstrated that anandamide, but not 2-arachidonylglycerol, requires lipid raft-mediated events to inhibit cellular proliferation. Closer inspection of the lipid raft structures within the cell membrane revealed that although anandamide treatment had no observable effect 2-arachidonylglycerol treatment effectively dissipated the lipid raft structures and caused the lipid raft-associated proteins lyn and flotillin-1 to disperse into the surrounding membrane. In addition, anandamide, but not 2-arachidonylglycerol, induced an accumulation of ceramide, which was required for anandamide-induced suppression of cell growth. Finally we demonstrated that anandamide and ceramide treatment of cholangiocarcinoma cells recruited Fas and Fas ligand into the lipid rafts, subsequently activating death receptor pathways. These findings suggest that modulation of the endocannabinoid system may be a target for the development of possible therapeutic strategies for the treatment of this devastating cancer.

Received for publication, August 28, 2006 , and in revised form, February 26, 2007.

^* The study was supported by a grant award from Scott and White Hospital (to S. D.), the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology, a Veterans Affairs Research Scholar Award, a Veterans Affairs Merit Award, and National Institutes of Health Grant DK062975 (to G. A.). 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: Depts. of Medicine and Systems Biology and Translational Medicine, Central Texas Veterans Health Care System, Texas A&M University System Health Science Center College of Medicine, Medical Research Bldg., 702 S. W. H. K. Dodgen Loop, Temple, TX 76504. Tel.: 254-742-7044; Fax: 254-724-8070; E-mail: galpini{at}tamu.edu.

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