Monoacylglycerol Lipase Exerts Dual Control over Endocannabinoid and Fatty Acid Pathways to Support Prostate Cancer

The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Chemistry & biology (Impact Factor: 6.65). 07/2011; 18(7):846-56. DOI: 10.1016/j.chembiol.2011.05.009
Source: PubMed


Cancer cells couple heightened lipogenesis with lipolysis to produce fatty acid networks that support malignancy. Monoacylglycerol lipase (MAGL) plays a principal role in this process by converting monoglycerides, including the endocannabinoid 2-arachidonoylglycerol (2-AG), to free fatty acids. Here, we show that MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and that pharmacological or RNA-interference disruption of this enzyme impairs prostate cancer aggressiveness. These effects were partially reversed by treatment with fatty acids or a cannabinoid receptor-1 (CB1) antagonist, and fully reversed by cotreatment with both agents. We further show that MAGL is part of a gene signature correlated with epithelial-to-mesenchymal transition and the stem-like properties of cancer cells, supporting a role for this enzyme in protumorigenic metabolism that, for prostate cancer, involves the dual control of endocannabinoid and fatty acid pathways.

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Available from: Jonathan Z. Long, May 06, 2015
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    • "The prostate gland expresses a functional epithelial CB1 receptor, which in the rat is involved in the control of the contraction of the gland [6,7], and its expression is increased in prostate cancer (Pca) cells [8,9], as is the expression of several endocannabinoid metabolizing enzymes, such as fatty acid amide hydrolase (FAAH) [10,11], cyclooxygenase-2 [12], and acylglycerol kinase [13]. Data from cell cultures and animal models are consistent with the hypothesis that the circulating endocannabinoid system can dampen the proliferation and invasivity of Pca cells [14–17], although mitogenic effects of low concentrations of CB1 receptor agonists secondary to activation of the Akt signaling pathway have been described [18]. In Pca tumor samples, CB1 receptor scores and pAkt scores are correlated and show a significant interaction term in ordinal regression analyses with the Gleason score as the dependent variable [19]. "
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    ABSTRACT: BACKGROUND The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) → CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 → FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors. Prostate 74:1107–1117, 2014. © 2014 The Authors. The Prostate published by Wiley Periodicals, Inc.
    Full-text · Article · Aug 2014 · The Prostate
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    • "With respect to prostate cancer (Pca) cells, Nithipatikom et al.[2] reported that compounds reducing the synthesis of the endocannabinoid ligand 2-arachidonoylglycerol (2-AG) increased the invasivity of the cells in vitro, whereas the reverse was seen when the metabolism of this endocannabinoid was blocked. A subsequent study reported that a selective blockade of the primary 2-AG metabolising enzyme monoacylglycerol lipase (MGL), either by use of the selective MGL inhibitor JZL184 or by shRNA knockdown of the enzyme, affected cell survival and invasion in vitro and reduced tumour growth in a xenograft model [3]. This effect was due in part to activation of CB1 receptors by the increased 2-AG concentration, and in part to blockade of the production of long chain fatty acids by the MGL-catalysed hydrolysis of the corresponding monoacylglycerols [3]. "
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    ABSTRACT: Background It has been reported that direct activation of the cannabinoid CB1 receptor in epidermal growth factor (EGR)-stimulated PC-3 prostate cancer cells results in an anti-proliferative effect accompanied by a down-regulation of EGF receptors (EGFR). In the present study, we investigated whether similar effects are seen following inhibition of the endocannabinoid hydrolytic enzyme monoacylglycerol lipase (MGL). Results CB1 receptor expression levels were found to differ greatly between two experimental series conducted using PC-3 cells. The monoacylglycerol lipase inhibitor JZL184 increased levels of 2-arachidonoylglycerol in the PC-3 cells without producing changes in the levels of anandamide and related N-acylethanolamines. In the first series of experiments, JZL184 produced a small mitogenic effect for cells that had not been treated with EGF, whereas an anti-proliferative effect was seen for EGF-treated cells. An anti-proliferative effect for the EGF-treated cells was also seen with the CB receptor agonist CP55,940. In the second batch of cells, there was an interaction between JZL184 and CB1 receptor expression densities in linear regression analyses with EGFR expression as the dependent variable. Conclusions Inhibition of MGL by JZL184 can affect EGFR expression. However, the use in our hands of PC-3 cells as a model to investigate the therapeutic potential of MGL inhibitors and related compounds is compromised by their variability of CB1 receptor expression.
    Full-text · Article · Jul 2014 · BMC Research Notes
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    • "Dysregulated lipid flux in obesity results in decreased HDL cholesterol and elevated LDL, circulating levels of triglycerides and free fatty acids which have been shown to promote prostate cancer cell survival [24, 25]. Inflammatory lipid mediators such as arachidonate and downstream signalling lipids, such as eicosanoids, prostanoids, and leukotrienes, are also increased [21, 26] and could potentially impact tumour cell biology; arachidonate can also promote steroid hormone production in prostate cancer cells [27]. "
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    ABSTRACT: Obesity and type 2 diabetes are recognised risk factors for the development of some cancers and, increasingly, predict more aggressive disease, treatment failure, and cancer-specific mortality. Many factors may contribute to this clinical observation. Hyperinsulinaemia, dyslipidaemia, hypoxia, ER stress, and inflammation associated with expanded adipose tissue are thought to be among the main culprits driving malignant growth and cancer advancement. This observation has led to the proposal of the potential utility of "old players" for the treatment of type 2 diabetes and metabolic syndrome as new cancer adjuvant therapeutics. Androgen-regulated pathways drive proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen deprivation therapy (ADT) exploits this dependence to systemically treat advanced prostate cancer resulting in anticancer response and improvement of cancer symptoms. However, the initial therapeutic response from ADT eventually progresses to castrate resistant prostate cancer (CRPC) which is currently incurable. ADT rapidly induces hyperinsulinaemia which is associated with more rapid treatment failure. We discuss current observations of cancer in the context of obesity, diabetes, and insulin-lowering medication. We provide an update on current treatments for advanced prostate cancer and discuss whether metabolic dysfunction, developed during ADT, provides a unique therapeutic window for rapid translation of insulin-sensitising medication as combination therapy with antiandrogen targeting agents for the management of advanced prostate cancer.
    Full-text · Article · Mar 2013 · International Journal of Cell Biology
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