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

Nomura, Daniel K.; Lombardi, Donald P.; Chang, Jae Won; Niessen, Sherry; Ward, Anna M.; Long, Jonathan Z.; Hoover, Heather; Cravatt, Benjamin F.

doi:10.1016/j.chembiol.2011.05.009

Cited by 231 publications

(244 citation statements)

References 55 publications

(108 reference statements)

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“…S1A). We have reported that these aggressive cancer cells have heightened migratory, invasive, and tumorigenic properties compared with less aggressive cells (17)(18)(19). We also show that AGPS expression is elevated two-to fourfold in Nottingham grade I (low-grade), II (intermediate-grade), and III (high-grade) primary human breast tumors (Fig.…”

Section: Resultsmentioning

confidence: 56%

Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity

Benjamin

Cozzo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

168

186

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Aberrant lipid metabolism is an established hallmark of cancer cells. In particular, ether lipid levels have been shown to be elevated in tumors, but their specific function in cancer remains elusive. We show here that the metabolic enzyme alkylglyceronephosphate synthase (AGPS), a critical step in the synthesis of ether lipids, is up-regulated across multiple types of aggressive human cancer cells and primary tumors. We demonstrate that ablation of AGPS in cancer cells results in reduced cell survival, cancer aggressiveness, and tumor growth through altering the balance of ether lipid, fatty acid, eicosanoid, and fatty acidderived glycerophospholipid metabolism, resulting in an overall reduction in the levels of several oncogenic signaling lipids. Taken together, our results reveal that AGPS, in addition to maintaining ether lipids, also controls cellular utilization of fatty acids, favoring the generation of signaling lipids necessary for promoting the aggressive features of cancer.cancer metabolism | metabolomics | lipid signaling lysophosphatidic acid | eicosanoids

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Section: Resultsmentioning

confidence: 56%

Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity

Benjamin

Cozzo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

168

186

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“…Interestingly, Mgll is part of the endocannabinoid system and it was shown to be a lipolytic enzyme able to free fatty acids, generating prooncogenic metabolites such as lipophosphatidic acid and prostaglandins. 19 Indeed, chemical and genetic inhibitions of Mgll impair cancer cell proliferation, migration, invasion and tumor growth in xenograft models, 19,20,26 suggesting Mgll as a relevant target for cancer treatment. It is of note that among Prdm5 targets we identified other targets involved in lipid metabolism, such as ATP citrate lyase, which is the enzyme converting citrate to cytosolic acetyl-CoA in the first step of fatty acid synthesis.…”

Section: Discussionmentioning

confidence: 99%

Prdm5 suppresses ApcMin-driven intestinal adenomas and regulates monoacylglycerol lipase expression

et al. 2013

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PRDM proteins are tissue-specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancer types of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an Apc Min background. By using the genome-wide ChIP-seq (chromatin immunoprecipitation (ChIP) followed by DNA sequencing) and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis, and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor-suppressive functions of PRDM5.

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“…The DAGL ␣ cDNA 2-arachidonoylglycerol, has been implicated in the control of pain mechanisms ( 13 ) and cancer cell proliferation ( 14 ). DAGL enzymes have been found to be important in the production of 2-arachidonoylglycerol and in the control of appetite and pain ( 15 ) and also in the regulation of Ca 2+ infl ux into cells ( 16 ).…”

Section: Sn -1-dagl Assaymentioning

confidence: 99%

Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors

Iglesias

Lamontagne

Erb

et al. 2016

Journal of Lipid Research

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is also an important source of several metabolic signals. As an integral part of the glycerolipid/fatty acid cycle ( 1 ), lipolysis produces lipid signals that modify cellular functions such as glucose-stimulated insulin secretion ( 2 ) and metabolic pathways and also alter transcription of various genes ( 1, 3 ). TG breakdown to glycerol and fatty acids is accomplished by the sequential action of adipose triglyceride lipase (ATGL), which hydrolyzes TG to 2,3-or 1,3-diacylglycerol (DAG), followed by hormone sensitive lipase (HSL)-mediated DAG hydrolysis to generate 1-or 2-monoacylglycerol (MAG) ( 1, 3 ). Finally MAG is hydrolyzed by either the classical MAG lipase (MAGL) or the recently described ␣ / ␤ -hydrolase domain 6 (ABHD6) to glycerol and FFA ( 4-6 ). Receptor-mediated signaling at the plasma membrane leads to the phospholipase-C-dependent formation of 1,2-DAG, which is further hydrolyzed by sn -1-DAG lipases (DAGL) ␣ or ␤ ( 7 ), to form mostly 2-MAG.Recent studies indicated the physiological importance of many of these lipases. Thus, ATGL has been implicated in lipid homeostasis in adipocytes, myocardium and skeletal muscle, cancer cachexia ( 1,3,8 ), and the regulation of insulin secretion in pancreatic ␤ -cells ( 9 ). HSL was shown to be important in adipose lipid metabolism ( 10 ) and in the regulation of glucose-stimulated insulin secretion ( 11,12 ). MAGL, which hydrolyzes the endocannabinoid Abstract Lipids are used as cellular building blocks and condensed energy stores and also act as signaling molecules. The glycerolipid/ fatty acid cycle, encompassing lipolysis and lipogenesis, generates many lipid signals. Reliable procedures are not available for measuring activities of several lipolytic enzymes for the purposes of drug screening, and this resulted in questionable selectivity of various known lipase inhibitors. We now describe simple assays for lipolytic enzymes, including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), sn -1-diacylglycerol lipase (DAGL), monoacylglycerol lipase, ␣ / ␤ -hydrolase domain 6, and carboxylesterase 1 (CES1) using recombinant human and mouse enzymes either in cell extracts or using purifi ed enzymes. We observed that many of the reported inhibitors lack specifi city. Thus, Cay10499 (HSL inhibitor) and RHC20867 (DAGL inhibitor) also inhibit other lipases. Marked differences in the inhibitor sensitivities of human ATGL and HSL compared with the corresponding mouse enzymes was noticed. Thus, ATGListatin inhibited mouse ATGL but not human ATGL, and the HSL inhibitors WWL11 and Compound 13f were effective against mouse enzyme but much less potent against human enzyme. Many of these lipase inhibitors also inhibited human CES1. Results describe reliable assays for measuring lipase activities that are amenable for drug screening and also caution about the specifi city of the many earlier described lipase inhibitors.

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

Cited by 231 publications

References 55 publications

Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity

Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity

Prdm5 suppresses ApcMin-driven intestinal adenomas and regulates monoacylglycerol lipase expression

Simplified assays of lipolysis enzymes for drug discovery and specificity assessment of known inhibitors

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