Opposing actions of endocannabinoids on cholangiocarcinoma growth - Recruitment of Fas and Fas ligand to lipid rafts

被引:87
作者
DeMorrow, Sharon
Glaser, Shannon
Francis, Heather
Venter, Julie
Vaculin, Bradley
Vaculin, Shelley
Alpini, Gianfranco
机构
[1] Texas A&M Univ Syst, Hlth Sci Ctr, Dept Med, Coll Med, Temple, TX 76504 USA
[2] Cent Texas Vet Hlth Care Syst, Temple, TX USA
[3] Scott & White Hosp, Dept Med, Temple, TX USA
[4] Scott & White Hosp, Dept Syst Biol & Translat Med, Temple, TX USA
[5] Scott & White Hosp, Div Res & Educ, Temple, TX USA
关键词
D O I
10.1074/jbc.M608238200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-beta- 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.
引用
收藏
页码:13098 / 13113
页数:16
相关论文
共 85 条
[32]   Methanandamide increases COX-2 expression and tumor growth in murine lung cancer [J].
Gardner, B ;
Zhu, LX ;
Sharma, S ;
Tashkin, DP ;
Dubinett, SM .
FASEB JOURNAL, 2003, 17 (12) :2157-+
[33]  
Giuliano M, 2006, INT J MOL MED, V17, P811
[34]   Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528:: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system [J].
Griffin, G ;
Wray, EJ ;
Tao, Q ;
McAllister, SD ;
Rorrer, WK ;
Aung, MM ;
Martin, BR ;
Abood, ME .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1999, 377 (01) :117-125
[35]   REGULATION OF INTRACELLULAR PH BY IMMORTALIZED HUMAN INTRAHEPATIC BILIARY EPITHELIAL-CELL LINES [J].
GRUBMAN, SA ;
PERRONE, RD ;
LEE, DW ;
MURRAY, SL ;
ROGERS, LC ;
WOLKOFF, LI ;
MULBERG, AE ;
CHERINGTON, V ;
JEFFERSON, DM .
AMERICAN JOURNAL OF PHYSIOLOGY, 1994, 266 (06) :G1060-G1070
[36]   Ceramide and cell death receptor clustering [J].
Gulbins, E ;
Grassmé, H .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 2002, 1585 (2-3) :139-145
[37]   A pilot clinical study of Δ9- tetrahydrocannabinol in patients with recurrent glioblastoma multiforme [J].
Guzman, M. ;
Duarte, M. J. ;
Blazquez, C. ;
Ravina, J. ;
Rosa, M. C. ;
Galve-Roperh, I. ;
Sanchez, C. ;
Velasco, G. ;
Gonzalez-Feria, L. .
BRITISH JOURNAL OF CANCER, 2006, 95 (02) :197-203
[38]   Up-regulation of cyclooxygenase-2 expression is involved in R(+)-methanandamide-induced apoptotic death of human neuroglioma cells [J].
Hinz, B ;
Ramer, R ;
Eichele, K ;
Weinzierl, U ;
Brune, K .
MOLECULAR PHARMACOLOGY, 2004, 66 (06) :1643-1651
[39]   R(+)-methanandamide-induced cyclooxygenase-2 expression in H4 human neuroglioma cells:: possible involvement of membrane lipid rafts [J].
Hinz, B ;
Ramer, R ;
Eichele, K ;
Weinzierl, U ;
Brune, K .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2004, 324 (02) :621-626
[40]   Anandamide-induced neuroblastoma cell rounding via the CBI cannabinoid receptors [J].
Ishii, I ;
Chun, J .
NEUROREPORT, 2002, 13 (05) :593-596