title: Cannabinoid receptor type 1 (CB1) activation inhibits small GTPase RhoA activity and regulates motility of prostate carcinoma cells.
abstract: The cannabinoid receptor type 1 (CB1) is a G protein-coupled receptor that is activated in an autocrine fashion by the endocannabinoids (EC), N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). The CB1 and its endogenous and synthetic agonists are emerging as therapeutic targets in several cancers due to their ability to suppress carcinoma cell invasion and migration. However, the mechanisms that the CB1 regulates cell motility are not well understood. In this study, we examined the molecular mechanisms that diminish cell migration upon the CB1 activation in prostate carcinoma cells. The CB1 activation with the agonist WIN55212 significantly diminishes the small GTPase RhoA activity but modestly increases the Rac1 and Cdc42 activity. The diminished RhoA activity is accompanied by the loss of actin/myosin microfilaments, cell spreading, and cell migration. Interestingly, the CB1 inactivation with the selective CB1 antagonist AM251 significantly increases RhoA activity, enhances microfilament formation and cell spreading, and promotes cell migration. This finding suggests that endogenously produced EC activate the CB1, resulting in chronic repression of RhoA activity and cell migration. Consistent with this possibility, RhoA activity is significantly diminished by the exogenous application of AEA but not by 2-AG in PC-3 cells (cells with very low AEA hydrolysis). Pretreatment of cells with a monoacylglycerol lipase inhibitor, JZL184, which blocks 2-AG hydrolysis, decreases the RhoA activity. These results indicate the unique CB1 signaling and support the model that EC, through their autocrine activation of CB1 and subsequent repression of RhoA activity, suppress migration in prostate carcinoma cells.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA. kasemn@mcw.edu
authors.forename: Kasem
authors.initials: K
authors.lastname: Nithipatikom
authors.forename: Ana Doris
authors.initials: AD
authors.lastname: Gomez-Granados
authors.forename: Alan T
authors.initials: AT
authors.lastname: Tang
authors.forename: Adam W
authors.initials: AW
authors.lastname: Pfeiffer
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
authors.forename: William B
authors.initials: WB
authors.lastname: Campbell
mesh_terms: D000199:Actins / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009218:Myosins / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: D000199:Actins; D001095:Arachidonic Acids; D048588:Benzoxazines; D063388:Endocannabinoids; D005989:Glycerides; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; C107953:RAC1 protein, human; D043884:Receptor, Cannabinoid, CB1; C066737:RHOA protein, human; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; D009218:Myosins; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C078814:anandamide
references.citation: J Biol Chem. 2008 Jan 11;283(2):963-76
references.pmid: 17951244
references.citation: J Pharmacol Exp Ther. 2010 Feb;332(2):336-44
references.pmid: 19889794
references.citation: Circ Res. 2008 May 23;102(10):1265-74
references.pmid: 18420945
references.citation: Mol Cell Biol. 2009 Nov;29(22):6018-32
references.pmid: 19737918
references.citation: Oncol Rep. 2007 Apr;17(4):813-6
references.pmid: 17342320
references.citation: J Biochem. 2008 Nov;144(5):685-90
references.pmid: 18806270
references.citation: Cell. 2003 Feb 21;112(4):453-65
references.pmid: 12600310
references.citation: Cancer Res. 2008 Jan 15;68(2):339-42
references.pmid: 18199524
references.citation: Exp Cell Res. 2006 Feb 15;312(4):363-73
references.pmid: 16343481
references.citation: J Cell Biol. 1999 Nov 29;147(5):1009-22
references.pmid: 10579721
references.citation: J Biol Chem. 1999 Jun 25;274(26):18675-85
references.pmid: 10373480
references.citation: Cancer Lett. 2006 Feb 20;233(1):36-47
references.pmid: 16473668
references.citation: Oncogene. 2006 Sep 28;25(44):5942-52
references.pmid: 16652149
references.citation: Cancer Res. 2008 Aug 1;68(15):6468-76
references.pmid: 18676872
references.citation: Proc Soc Exp Biol Med. 2000 Oct;225(1):1-8
references.pmid: 10998193
references.citation: Am J Physiol Renal Physiol. 2005 Apr;288(4):F763-70
references.pmid: 15572519
references.citation: J Med Chem. 2004 Jun 3;47(12):3048-57
references.pmid: 15163186
references.citation: Biochem J. 2000 Jun 1;348 Pt 2:241-55
references.pmid: 10816416
references.citation: Biochem Biophys Res Commun. 2005 Jul 15;332(4):1028-33
references.pmid: 15919052
references.citation: J Cell Biol. 1997 Nov 3;139(3):797-807
references.pmid: 9348295
references.citation: Cancer Res. 2004 Dec 15;64(24):8826-30
references.pmid: 15604240
references.citation: J Cell Sci. 2007 Feb 1;120(Pt 3):502-11
references.pmid: 17227793
references.citation: Curr Opin Investig Drugs. 2010 Jan;11(1):51-62
references.pmid: 20047159
references.citation: J Biol Chem. 2000 Oct 6;275(40):31001-8
references.pmid: 10896672
references.citation: Endocr Relat Cancer. 2008 Dec;15(4):965-74
references.pmid: 18676619
references.citation: Cancer Res. 2008 Jan 1;68(1):115-21
references.pmid: 18172303
references.citation: Curr Cancer Drug Targets. 2004 Jun;4(4):345-54
references.pmid: 15180500
references.citation: J Biol Chem. 2006 Sep 8;281(36):26483-90
references.pmid: 16787920
references.citation: J Biol Chem. 2000 Jul 14;275(28):21722-9
references.pmid: 10783386
references.citation: J Hypertens. 2005 May;23(5):1037-45
references.pmid: 15834290
references.citation: Int J Cancer. 2008 Sep 15;123(6):1318-26
references.pmid: 18566995
references.citation: Dev Biol. 2004 Jan 1;265(1):23-32
references.pmid: 14697350
references.citation: J Med Chem. 2006 Oct 5;49(20):5969-87
references.pmid: 17004712
references.citation: Br J Pharmacol. 2008 Jan;153(2):179-81
references.pmid: 17994111
references.citation: Int J Biochem Cell Biol. 2004 Oct;36(10):1890-909
references.pmid: 15203104
references.citation: Trends Cell Biol. 2005 Jul;15(7):356-63
references.pmid: 15921909
references.citation: Curr Opin Hematol. 2005 Jan;12(1):14-21
references.pmid: 15604886
references.citation: Biochemistry. 2010 Jan 26;49(3):502-11
references.pmid: 20025243
references.citation: Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9668-70
references.pmid: 1946384
references.citation: Exp Cell Res. 2008 Apr 15;314(7):1540-52
references.pmid: 18316075
references.citation: FASEB J. 2003 Sep;17(12):1771-3
references.pmid: 12958205
references.citation: Int J Cancer. 2007 Sep 1;121(5):984-91
references.pmid: 17443494
references.citation: J Pharmacol Exp Ther. 2008 Apr;325(1):341-8
references.pmid: 18174385
references.citation: Mol Carcinog. 2006 Jul;45(7):518-29
references.pmid: 16402387
references.citation: Biochemistry. 2003 Jan 28;42(3):702-9
references.pmid: 12534282
references.citation: EMBO J. 1996 Feb 1;15(3):510-9
references.pmid: 8599934
references.citation: Cancer Res. 2003 Mar 15;63(6):1359-64
references.pmid: 12649199
references.citation: Biochem J. 2002 Jan 15;361(Pt 2):243-54
references.pmid: 11772396
references.citation: J Cell Biochem. 2007 Aug 1;101(5):1292-300
references.pmid: 17492768
references.citation: Mol Biol Cell. 2002 Mar;13(3):902-14
references.pmid: 11907271