title: Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation.
abstract: Anandamide and 2-arachidonoylglycerol (2-AG), two endogenous ligands of the CB1 and CB2 cannabinoid receptor subtypes, inhibit the proliferation of PRL-responsive human breast cancer cells (HBCCs) through down-regulation of the long form of the PRL receptor (PRLr). Here we report that 1) anandamide and 2-AG inhibit the nerve growth factor (NGF)-induced proliferation of HBCCs through suppression of the levels of NGF Trk receptors; 2) inhibition of PRLr levels results in inhibition of the proliferation of other PRL-responsive cells, the prostate cancer DU-145 cell line; and 3) CB1-like cannabinoid receptors are expressed in HBCCs and DU-145 cells and mediate the inhibition of cell proliferation and Trk/PRLr expression. Beta-NGF-induced HBCC proliferation was potently inhibited (IC50 = 50-600 nM) by the synthetic cannabinoid HU-210, 2-AG, anandamide, and its metabolically stable analogs, but not by the anandamide congener, palmitoylethanolamide, or the selective agonist of CB2 cannabinoid receptors, BML-190. The effect of anandamide was blocked by the CB1 receptor antagonist, SR141716A, but not by the CB2 receptor antagonist, SR144528. Anandamide and HU-210 exerted a strong inhibition of the levels of NGF Trk receptors as detected by Western immunoblotting; this effect was reversed by SR141716A. When induced by exogenous PRL, the proliferation of prostate DU-145 cells was potently inhibited (IC50 = 100-300 nM) by anandamide, 2-AG, and HU-210. Anandamide also down-regulated the levels of PRLr in DU-145 cells. SR141716A attenuated these two effects of anandamide. HBCCs and DU-145 cells were shown to contain 1) transcripts for CB1 and, to a lesser extent, CB2 cannabinoid receptors, 2) specific binding sites for [3H]SR141716A that could be displaced by anandamide, and 3) a CB1 receptor-immunoreactive protein. These findings suggest that endogenous cannabinoids and CB1 receptor agonists are potential negative effectors of PRL- and NGF-induced biological responses, at least in some cancer cells.
authors.affiliation: Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, Arco Felice (NA), Italy.
authors.forename: D
authors.initials: D
authors.lastname: Melck
authors.forename: L
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: P
authors.initials: P
authors.lastname: Orlando
authors.forename: T
authors.initials: T
authors.lastname: Bisogno
authors.forename: C
authors.initials: C
authors.lastname: Laezza
authors.forename: M
authors.initials: M
authors.lastname: Bifulco
authors.forename: V
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D001095:Arachidonic Acids / Q000494:pharmacology; D001665:Binding Sites; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D011471:Prostatic Neoplasms / Q000473:pathology*; D011720:Pyrazoles / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000077285:Rimonabant; D014407:Tumor Cells, Cultured
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; D009414:Nerve Growth Factors; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017475:Receptors, Nerve Growth Factor; D011981:Receptors, Prolactin; C094503:glyceryl 2-arachidonate; D020794:Receptor Protein-Tyrosine Kinases; D000077285:Rimonabant; C078814:anandamide