Diverse roles of 2‐arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12‐lipoxygenase metabolism

Endsley, Michael P.; Aggarwal, Nidhi; Isbell, Marilyn A.; Wheelock, Craig E.; Hammock, Bruce D.; Falck, John R.; Campbell, William B.; Nithipatikom, Kasem

doi:10.1002/ijc.22761

Cited by 49 publications

(43 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results indicated that transfection with EPHX1 cDNA markedly increased the EPHX1 protein and cSO hydrolysis activity. Despite a very low endogenous expression of EPHX1 protein in PC-3 cells, these cells have a relatively high 2-AG hydrolysis ( 28 ) in the control cells. Other enzymes metabolizing 2-AG contributed to 2-AG hydrolysis as refl ected by the smaller increase of 2-AG hydrolysis than the increase of cSO hydrolysis ( Fig.…”

Section: Discussionmentioning

confidence: 87%

A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol

Nithipatikom

Endsley

Pfeiffer

et al. 2014

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

including environmental chemicals and many therapeutic drugs. This enzymatic action converts lipophilic and sometimes reactive epoxides to more polar 1,2-diols. It also activates (pro)toxins and (pro)carcinogens ( 1, 2 ). In addition to xenobiotic metabolism, EPHX1 regulates endogenous steroid metabolism ( 3 ), bile acid transportation ( 4 ), and the vitamin K1 reductase complex that is responsible for vitamin K1 oxide reduction activity ( 5 ). While a number of diverse functions of EPHX1 have been demonstrated, only a few naturally endogenous substrates for EPHX1 have been characterized ( 3,(6)(7)(8).2-Arachidonoylglycerol (2-AG) is a highly abundant endogenous ligand for the cannabinoid receptor type 1 (CB1) ( 9-11 ). Through the activation of CB1, 2-AG plays a major role in a variety of physiological processes. The actions of 2-AG are tightly regulated by enzymatic hydrolysis, a major deactivation pathway. Monoacylglycerol lipase (MGL) ( 12, 13 ) and possibly FA amide hydrolase (FAAH) ( 14 ) are responsible for hydrolysis of 2-AG to free arachidonic acid (AA) and glycerol. Non-FAAH or non-MGL enzymes in porcine membranes ( 15 ) and mouse microglial cells ( 16 ) have been demonstrated to hydrolyze 2-AG. Recent studies discovered two integral membrane enzymes, ␣ / ␤ -hydrolase fold 6 and 12, that contributed to ‫ف‬ 4% and 9% of total 2-AG hydrolysis, respectively, in mouse brain membrane ( 17,18 ).The amino acid sequence of human EPHX1 indicates an epoxide hydrolase N terminus at the amino acids 50- Microsomal epoxide hydrolase (EPHX1, EC 3.3.2.9) is a xenobiotic metabolizing enzyme that is functionally associated with the cytochrome P450 family. The commonly known function of EPHX1 is to metabolize xenobiotics

show abstract

Section: Discussionmentioning

confidence: 87%

A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol

Nithipatikom

Endsley

Pfeiffer

et al. 2014

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Among MAGs, the principal signaling molecule is the endocannabinoid 2-AG, which activates the CB1 and CB2 receptors (Ahn et al, 2008; Mackie and Stella, 2006). The endocannabinoid system has been implicated previously in cancer progression and, depending on the specific study, shown to promote (Sarnataro et al, 2006; Zhao et al, 2005) or suppress (Endsley et al, 2007; Wang et al, 2008) cancer pathogenesis. We therefore tested whether enhanced endocannabinoid signaling (resulting from elevated levels of 2-AG) might mediate the anti-migratory effects observed in MAGL-disrupted cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis

Nomura

Long

Niessen

et al. 2010

Cell

856

903

View full text Add to dashboard Cite

Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer pathogenesis, however, remains unknown. Here, we show that the enzyme monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in non-aggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity -- phenotypes that are reversed by an MAGL inhibitor. Interestingly, impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of pro-tumorigenic signals.

show abstract

“…The conflicting actions of 2-AG have been evidenced when looking at the invasive properties of prostate carcinoma cells as well. Endogenous 2-AG was anti-invasive whereas cells treated with high doses of 2-AG saw their invasiveness enhanced [36]. However, we allow for the possibility that URB597 could also exert cytotoxic effects independent of its action on AEA hydrolysis.…”

Section: Discussionmentioning

confidence: 98%

Increasing Antiproliferative Properties of Endocannabinoids in N1E-115 Neuroblastoma Cells through Inhibition of Their Metabolism

et al. 2011

View full text Add to dashboard Cite

The antitumoral properties of endocannabinoids received a particular attention these last few years. Indeed, these endogenous molecules have been reported to exert cytostatic, apoptotic and antiangiogenic effects in different tumor cell lines and tumor xenografts. Therefore, we investigated the cytotoxicity of three N-acylethanolamines – N-arachidonoylethanolamine (anandamide, AEA), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA) - which were all able to time- and dose-dependently reduce the viability of murine N1E-115 neuroblastoma cells. Moreover, several inhibitors of FAAH and NAAA, whose presence was confirmed by RT-PCR in the cell line, induced cell cytotoxicity and favored the decrease in cell viability caused by N-acylethanolamines. The most cytotoxic treatment was achieved by the co-incubation of AEA with the selective FAAH inhibitor URB597, which drastically reduced cell viability partly by inhibiting AEA hydrolysis and consequently increasing AEA levels. This combination of molecules synergistically decreased cell proliferation without inducing cell apoptosis or necrosis. We found that these effects are independent of cannabinoid, TRPV1, PPARα, PPARγ or GPR55 receptors activation but seem to occur through a lipid raft-dependent mechanism. These findings further highlight the interest of targeting the endocannabinoid system to treat cancer. More particularly, this emphasizes the great potential benefit of designing novel anti-cancerous therapies based on the association of endocannabinoids and inhibitors of their hydrolysis.

show abstract

Diverse roles of 2‐arachidonoylglycerol in invasion of prostate carcinoma cells: Location, hydrolysis and 12‐lipoxygenase metabolism

Cited by 49 publications

References 49 publications

A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol

A novel activity of microsomal epoxide hydrolase: metabolism of the endocannabinoid 2-arachidonoylglycerol

Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis

Increasing Antiproliferative Properties of Endocannabinoids in N1E-115 Neuroblastoma Cells through Inhibition of Their Metabolism

Contact Info

Product

Resources

About