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

被引:231
作者
Melck, D
De Petrocellis, L
Orlando, P
Bisogno, T
Laezza, C
Bifulco, M
Di Marzo, V
机构
[1] CNR, Ist Chim Mol Interesse Biol, I-80072 Arco Felice Napoli, NA, Italy
[2] CNR, Ist Cibernet, I-80072 Arco Felice Napoli, NA, Italy
[3] CNR, Ist Biochim Proteine & Enzimol, I-80072 Arco Felice Napoli, NA, Italy
[4] CNR, Ctr Endocrinol & Oncol Sperimentale, I-80131 Naples, Italy
[5] Univ Naples Federico II, Dipartimento Biol & Patol Cellulaire & Mol, I-80131 Naples, Italy
关键词
D O I
10.1210/en.141.1.118
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. P-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 [H-3]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 effecters of PRL- and NGF-induced biological responses, at least in some cancer cells.
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页码:118 / 126
页数:9
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