Identification of the major prostaglandin glycerol ester hydrolase in human cancer cells.

Manna JD, Wepy JA, Hsu KL, Chang JW, Cravatt BF, Marnett LJ
J Biol Chem. 2014 289 (49): 33741-53

PMID: 25301951 · PMCID: PMC4256310 · DOI:10.1074/jbc.M114.582353

Prostaglandin glycerol esters (PG-Gs) are produced as a result of the oxygenation of the endocannabinoid, 2-arachidonoylglycerol, by cyclooxygenase 2. Understanding the role that PG-Gs play in a biological setting has been difficult because of their sensitivity to enzymatic hydrolysis. By comparing PG-G hydrolysis across human cancer cell lines to serine hydrolase activities determined by activity-based protein profiling, we identified lysophospholipase A2 (LYPLA2) as a major enzyme responsible for PG-G hydrolysis. The principal role played by LYPLA2 in PGE2-G hydrolysis was confirmed by siRNA knockdown. Purified recombinant LYPLA2 hydrolyzed PG-Gs in the following order of activity: PGE2-G > PGF2α-G > PGD2-G; LYPLA2 hydrolyzed 1- but not 2-arachidonoylglycerol or arachidonoylethanolamide. Chemical inhibition of LYPLA2 in the mouse macrophage-like cell line, RAW264.7, elicited an increase in PG-G production. Our data indicate that LYPLA2 serves as a major PG-G hydrolase in human cells. Perturbation of this enzyme should enable selective modulation of PG-Gs without alterations in endocannabinoids, thereby providing a means to decipher the unique functions of PG-Gs in biology and disease.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (22)

Animals Arachidonic Acids Cell Line, Tumor Cyclooxygenase 2 Endocannabinoids Escherichia coli Esters Gene Expression Regulation, Neoplastic Glycerides Glycerol Humans Hydrolysis Kinetics Macrophages Mice Polyunsaturated Alkamides Prostaglandins Recombinant Proteins RNA, Small Interfering Signal Transduction Substrate Specificity Thiolester Hydrolases

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