Abstract
There is good evidence that the N-acylethanolamine (NAE)/monoacylglycerol (MAG) signalling systems are involved in the pathogenesis of cancer. However, it is not known how prostate tumours affect these systems in the surrounding non-malignant tissue and vice versa. In the present study we have investigated at the mRNA level 11 components of these systems (three coding for anabolic enzymes, two for NAE/MAG targets and six coding for catabolic enzymes) in rat prostate tissue following orthotopic injection of low metastatic AT1 cells and high metastatic MLL cells. The MLL tumours expressed higher levels of Napepld, coding for a key enzyme in NAE synthesis, and lower levels of Naaa, coding for the NAE hydrolytic enzyme N-acylethanolamine acid amide hydrolase than the AT1 tumours. mRNA levels of the components of the NAE/MAG signalling systems studied in the tissue surrounding the tumours were not overtly affected by the tumours. AT1 cells in culture expressed Faah, coding for the NAE hydrolytic enzyme fatty acid amide hydrolase, at much lower levels than Naaa. However, the ability of the intact cells to hydrolyse the NAE arachidonoylethanolamide (anandamide) was inhibited by an inhibitor of FAAH, but not of NAAA. Treatment of the AT1 cells with interleukin-6, a cytokine known to be involved in the pathogenesis of prostate cancer, did not affect the expression of the components of the NAE/MAG system studied. It is thus concluded that in the model system studied, the tumours show different expressions of mRNA coding for key the components of the NAE/MAG system compared to the host tissue, but that these changes are not accompanied by alterations in the non-malignant tissue.
Highlights
There is good evidence that the N-acylethanolamine (NAE)/monoacylglycerol (MAG) signalling systems are involved in the pathogenesis of cancer
NAEs are hydrolysed to their corresponding long-chain fatty acids by two enzymes, fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid
MAGs are hydrolysed by monoacylglycerol lipase (MAGL) and the α/β-hydrolase domain containing (ABHD) 6 and 12 enzymes4,5, 2-AG can act as a substrate for FAAH9
Summary
There is good evidence that the N-acylethanolamine (NAE)/monoacylglycerol (MAG) signalling systems are involved in the pathogenesis of cancer. For example, a reduction in AEA or 2-AG levels in the tumour due to over-expression of FAAH or MAGL would be expected to be deleterious by removing an antiproliferative substrate tone mediated by the ERK pathway[17,33], whereas an increased synthesis of these endocannabinoids could increase tumour cell proliferation in tumours with high CB1 receptor expression by opening up survival pathways[26]. Additional CB receptor-independent pathways may contribute: given the wide substrate specificity of FAAH and MAGL, increased expression will result in an increased production of long-chain fatty acids required to sustain tumour growth[35]
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