Abstract
Background: The concentrations of three N-acylethanolamines (NAEs), anandamide (AEA), N-oleoylethanolamide (OEA), and N-palmitylethanolamide (PEA) are increased in the endometria of women with endometrial cancer (EC). It is widely accepted that plasma levels of these three NAEs are regulated by the actions of the rate-limiting enzymes N-acylphoshatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), which are synthesizing and degradative, respectively. The expression and activity of these enzymes have not previously been studied in EC.Methods: FAAH activity in peripheral blood lymphocytes, and transcript and protein expression for FAAH and NAPE-PLD in EC tissues were measured using enzyme, quantitative RT-PCR, and histomorphometry (of immunoreactive tissue sections), respectively. Samples were from 6 post-menopausal women with atrophic endometria (controls) and 34 women with histologically diagnosed EC. Concentrations of the three NAEs also measured in plasma and tissues were correlated with lymphocytic FAAH activity and the NAPE-PLD and FAAH transcript and protein levels.Results: Peripheral lymphocyte FAAH activity was unaffected in women with EC compared to controls. The FAAH transcript expression level was significantly (p < 0.0001) 75% lower in EC whilst NAPE-PLD levels were not significantly (p = 0.798) increased. In line with the transcript data, a significant (p < 0.0001) tumor type-dependent 70–90% decrease in FAAH protein and significant 4- to 14-fold increase in NAPE-PLD protein (p < 0.0001) was observed in the malignant tissue with more advanced disease having lower FAAH and higher NAPE-PLD expression than less advanced disease. Correlation analyses also confirmed that tissue NAE concentrations were inversely related to FAAH expression and directly correlated to NAPE-PLD expression and the NAPE-PLD/FAAH ratio.Conclusion: These data support our previous observation of tissue levels of AEA, OEA, and PEA and a role for NAE metabolism in the pathogenesis of EC.
Highlights
The levels of the endocannabinoids N-arachidonylethanolamine, N-palmityolethanolamine (PEA), and Noleoylethanolamine (OEA) have been shown to be higher in endometrial cancer tissue of post-menopausal women when compared to that of controls [1]
There was a gradual decrease in levels of fatty acid amide hydrolase (FAAH) transcript with tumor grade; with the highest levels of 0.445 (0.230–0.720; median and interquartile range (IQR)) observed in atrophic endometria
An examination of the NAPE-PLD/FAAH ratios for the transcripts and proteins showed that both transcript (Figure 5G) and protein (Figure 5H) were significantly increased in the endometrial cancer (EC) tissue. Both FAAH and NAPE-PLD protein expression were altered in the endometria of women with EC when compared with atrophic controls; FAAH was decreased whilst NAPE-PLD was increased
Summary
The levels of the endocannabinoids N-arachidonylethanolamine (anandamide; AEA), N-palmityolethanolamine (PEA), and Noleoylethanolamine (OEA) have been shown to be higher in endometrial cancer tissue of post-menopausal women when compared to that of controls [1]. Since AEA, OEA and PEA levels are higher in endometrial cancer tissues [1], we adduced that either a reduction in FAAH expression, or an increase in NAPE-PLD expression, or both, occurring simultaneously, might be responsible for the observed higher tissue levels of these endocannabinoids (collectively referred to as Nacylethanolamines or NAEs). The implications of these observations and conclusions are that both the changes in NAEs and their enzymes might be involved in the pathogenesis of endometrial cancer. The expression and activity of these enzymes have not previously been studied in EC
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