Expression and Function of the Endocannabinoid Modulating Enzymes Fatty Acid Amide Hydrolase and N-Acylphosphatidylethanolamine-Specific Phospholipase D in Endometrial Carcinoma

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 Ayakannu et al. FAAH and NAPE-PLD Expression in Endometrial Cancer 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.

The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

“…The latter investigation also reported elevated 2-AG levels as a result of strong overexpression of DAGL α with less pronounced MAGL induction in hepatocellular cancer tissue; downregulation of AEA was found to be thereby dependent on higher expression levels of FAAH. In contrast to these observations, a decrease in FAAH protein expression and an increase in NAPE-PLD in cancerous versus non-cancerous endometrial tissue has recently been reported [61], resulting in increased AEA and PEA levels in cancerous endometrial tissue and in plasma from patients with endometrial carcinoma compared to volunteers with an atrophic endometrium [60].…”

Molecular Mechanism of Cannabinoids in Cancer Progression

“…Interestingly, AEA levels were elevated in lymphatic metastasis [ 25 ] and in endometrial cancer (EC) tissue compared to non-cancerous tissues. Moreover, FAAH was reduced while NAPE-PLD was increased in EC [ 26 ]. In another study, NAPE-PLD and MAGL expression was upregulated in colorectal cancer tissue [ 25 , 27 , 28 ], furthermore, high MAGL expression was indicative of a poor prognosis for patients compared to those with a low expression of MAGL [ 29 ].…”

Nitric oxide positively affects endometrial receptivity via FAAH and NAPE-PLD in vitro

“…Firstly, we measured the relative levels of the transcripts for FAAH and NAPE-PLD in the two cell lines. FAAH and NAPE-PLD have been shown to be expressed in endometrial carcinoma (Ayakannu et al, 2019) and Ishikawa cells (Fonseca et al, 2018). However, it was necessary to confirm that HEC-1A cells also express FAAH and NAPE-PLD (Figure 3).…”