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Endocannabinoids Leads to Inhibition of Prostate Cancer Cell Proliferation

Julie Gardener

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Suppression of Nerve Growth Factor Trk Receptors and Prolactin Receptors by Endocannabinoids Leads to Inhibition of Human Breast and Prostate Cancer Cell Proliferation
Dominique Melck, Luciano De Petrocellis, Pierangelo Orlando, Tiziana Bisogno, Chiara Laezza, Maurizio Bifulco and Vincenzo Di Marzo
Endocrinology January 1, 2000


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. β-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.

TWO RECEPTOR subtypes for marijuana’s psychoactive component, (−)-Δ9-tetrahydrocannabinol, one, named CB1, most abundant in the brain and some peripheral tissues, and the other, named CB2, almost exclusively expressed in immune cells, have been characterized to date (see Ref. 1 for review). These findings together with the discovery of two endogenous ligands for these receptors, N-arachidonoyl-ethanolamine (anandamide) (2) and 2-arachidonoylglycerol (2-AG) (3, 4), named endocannabinoids (ECs), led to the suggestion of the existence in mammals of an endogenous cannabinoid system. The metabolism and pharmacological properties of the ECs have been thoroughly investigated (see Refs. 5, 6, 7, 8, 9, 10 for recent reviews), and yet the physiological role of these metabolites is still a matter for speculation. Anandamide and/or 2-AG were suggested to participate in several physiopathological situations, ranging from the modulation of neuronal (6) and immune cell (7) function to neuroprotection (8), control of cardiovascular and endocrine functions (9, 10), and antinociception (11, 12). We recently reported that anandamide arrests selectively the proliferation of human breast cancer cells (HBCCs) by inhibiting DNA synthesis and the G1/S transition of the cell cycle (13). This effect is exerted through the activation of as yet unidentified cannabinoid-binding sites and via the down-modulation of the expression of the long form of the receptor (PRLr) of PRL, one of the endogenous hormones necessary to these cells to proliferate and differentiate (14). We also reported that anandamide together with its putative phospholipid biosynthetic precursor (5, 6, 15) and the amidohydrolase responsible for anandamide degradation (for a review, see Ref. 16) are present in HBCCs. Cis-9-octadecenoamide, a bioactive compound that inhibits anandamide hydrolysis (5), also exerts a weak antimitogenic action, probably by raising the levels of endogenous anandamide in HBCCs (17). These data suggest that anandamide may function as a local down-modulator of HBCC proliferation. The present study was aimed at providing answers to questions raised by our previous investigations. Are ECs also capable of inhibiting the mitogenic action induced by other growth factors? Is the proliferation of other PRL-responsive cancer cells also inhibited by these endogenous mediators? Is the antiproliferative effect of ECs mediated by the CB1 or the CB2 subtype of cannabinoid receptors? We have investigated whether and through what mechanism anandamide and 2-AG also inhibit the nerve growth factor (NGF)-induced proliferation of HBCCs and the PRL-induced proliferation of human prostate cancer cells.


Source with Charts, Graphs and Links: Suppression of Nerve Growth Factor Trk Receptors and Prolactin Receptors by Endocannabinoids Leads to Inhibition of Human Breast and Prostate Cancer Cell Proliferation
 
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