Suppression of nerve growth factor trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation

Anandamide and 2-arachidonoylglycerol (2-AG), two endogenous ligands of the CB1 and CB2 cannabinoid receptor subtypes, inhibit the proliferation of PR L-responsive human breast cancer cells (HBCCs) through down-regulation of t he 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 HBC Cs through suppression of the levels of NGF Trk. receptors; 2) inhibition o f PRLr levels results in inhibition of the proliferation of other PRL-respo nsive cells, the prostate cancer DU-145 cell line; and 3) CB1-like cannabin oid receptors are expressed in HBCCs and DU-145 cells and mediate the inhib ition of cell proliferation and Trk/PRLr expression. P-NGF-induced HBCC pro liferation was potently inhibited (IC50 = 50-600 nM) by the synthetic canna binoid HU-210, 2-AG, anandamide, and its metabolically stable analogs, but not by the anandamide congener, palmitoylethanolamide, or the selective ago nist of CB2 cannabinoid receptors, BML-190. The effect of anandamide was bl ocked by the CB1 receptor antagonist, SR141716A, but not by the CB2 recepto r antagonist, SR144528. Anandamide and HU-210 exerted a strong inhibition o f the levels of NGF Trk receptors as detected by Western immunoblotting; th is effect was reversed by SR141716A. When induced by exogenous PRL, the pro liferation of prostate DU-145 cells was potently inhibited (IC50 = 100-300 nM) by anandamide, 2-AG, and HU-210. Anandamide also down-regulated the lev els of PRLr in DU-145 cells. SR141716A attenuated these two effects of anan damide. HBCCs and DU-145 cells were shown to contain 1) transcripts for CB1 and, to a lesser extent, CB2 cannabinoid receptors, 2) specific binding si tes for [H-3]SR141716A that could be displaced by anandamide, and 3) a CB1 receptor-immunoreactive protein. These findings suggest that endogenous can nabinoids and CB1 receptor agonists are potential negative effecters of PRL - and NGF-induced biological responses, at least in some cancer cells.