Palmitoylethanolamide inhibits the expression of fatty acid amide hydrolase and enhances the anti-proliferative effect of anandamide in human breast cancer cells

Abstract

Palmitoylethanolamide (PEA) has been shown to act in synergy with anandamide (arachidonoylethanolamide; AEA), an endogenous agonist of cannabinoid receptor type 1 (CB(1)). This synergistic effect was reduced by the CB(2) cannabinoid receptor antagonist SR144528, although PEA does not activate either CB(1) or CB(2) receptors. Here we show that PEA potently enhances the anti-proliferative effects of AEA on human breast cancer cells (HBCCs), in part by inhibiting the expression of fatty acid amide hydrolase (FAAH), the major enzyme catalysing AEA degradation. PEA (1-10 microM) enhanced in a dose-related manner the inhibitory effect of AEA on both basal and nerve growth factor (NGF)-induced HBCC proliferation, without inducing any cytostatic effect by itself. PEA (5 microM) decreased the IC(50) values for AEA inhibitory effects by 3-6-fold. This effect was not blocked by the CB(2) receptor antagonist SR144528, and was not mimicked by a selective agonist of CB(2) receptors. PEA enhanced AEA-evoked inhibition of the expression of NGF Trk receptors, which underlies the anti-proliferative effect of the endocannabinoid on NGF-stimulated MCF-7 cells. The effect of PEA was due in part to inhibition of AEA degradation, since treatment of MCF-7 cells with 5 microM PEA caused a approximately 30-40% down-regulation of FAAH expression and activity. However, PEA also enhanced the cytostatic effect of the cannabinoid receptor agonist HU-210, although less potently than with AEA. PEA did not modify the affinity of ligands for CB(1) or CB(2) receptors, and neither did it alter the CB(1)/CB(2)-mediated inhibitory effect of AEA on adenylate cyclase type V, nor the expression of CB(1) and CB(2) receptors in MCF-7 cells. We suggest that long-term PEA treatment of cells may positively affect the pharmacological activity of AEA, in part by inhibiting FAAH expression.

Regulation of circulating endocannabinoids associated with cancer and metastases in mice and humans

“…Endocannabinoids are involved in the regulation of several physiological systems that are involved in tumor development and tumor growth [6] as demonstrated by a disturbance of endocannabinoids in cancer in general, and specifically in metastatic cancer [4-7]. We showed a downregulation of ethanolamide endocannabinoids following local cancer induction in mice translated into cancer patients.…”

“…It is conceivable that the metabolism of ethanolamide endocannabinoids was increased in cancer. For example, FAAH is known to be upregulated in prostate, pancreatic, colon and breast cancer [25-28]. In addition, COX-2 is also known to be upregulated in various types of cancer [29].…”

“…Endocannabinoids inhibit tumor proliferation via direct effects on tumor cells [4] in breast, brain, skin, thyroid, prostate and colorectal cancers [5, 6] and via the suppression of angiogenesis and tumor invasion [7]. They contribute to failures of the immune system to attack tumors by favoring CB 2 mediated polarization of tumor-associated macrophages and dendritic cells toward tumor tolerance [8, 9].…”

Cannabinoids as therapeutic agents in cancer: current status and future implications

“…By contrast, CB2 immunoreactivity was detected in 72% of human breast tumor tissue and 91% of ErbB2-positive tumor tissue, suggesting a link between CB2 and ErbB2-expression [44]. The expression of CB2 receptor was also analyzed in different breast carcinoma cell lines (MCF-7, T-47D, MDA-MB-231, MDA-MB-468, EVSA-T, SkBr3) and human breast tissues [26, 44-46, 49, 51-52]. The putative novel cannabinoid receptor subtype GPR55 was highly expressed in a MDA-MB-231 cells, but it is expressed at lower (30-fold) levels in MCF-7 cells [53].…”

Mustard vesicants alter expression of the endocannabinoid system in mouse skin

“…In the skin, they also control keratinocyte proliferation, differentiation, and wound healing (Maccarrone et al, 2003; Ramot et al, 2013; Toth, Dobrosi, et al, 2011). Endocannabinoids function by binding to cannabinoid receptors and lipid signaling molecules such as the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) (Di Marzo et al, 2001; Dubrac et al, 2011; Kendall et al, 2013; O'Sullivan et al, 2010). Two major G protein-coupled endocannabinoid receptors have been identified in the skin, CB1 and CB2 (Galiegue et al, 1995; Kupczyk et al, 2009; Pertwee, 2014; Stander et al, 2005; Zheng et al, 2012).…”