title: Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer.
abstract: Cancer cells couple heightened lipogenesis with lipolysis to produce fatty acid networks that support malignancy. Monoacylglycerol lipase (MAGL) plays a principal role in this process by converting monoglycerides, including the endocannabinoid 2-arachidonoylglycerol (2-AG), to free fatty acids. Here, we show that MAGL is elevated in androgen-independent versus androgen-dependent human prostate cancer cell lines, and that pharmacological or RNA-interference disruption of this enzyme impairs prostate cancer aggressiveness. These effects were partially reversed by treatment with fatty acids or a cannabinoid receptor-1 (CB1) antagonist, and fully reversed by cotreatment with both agents. We further show that MAGL is part of a gene signature correlated with epithelial-to-mesenchymal transition and the stem-like properties of cancer cells, supporting a role for this enzyme in protumorigenic metabolism that, for prostate cancer, involves the dual control of endocannabinoid and fatty acid pathways.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. dnomura@berkeley.edu
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lombardi
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Anna M
authors.initials: AM
authors.lastname: Ward
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Heather H
authors.initials: HH
authors.lastname: Hoover
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D045744:Cell Line, Tumor; D063388:Endocannabinoids; D058750:Epithelial-Mesenchymal Transition; D005227:Fatty Acids / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005227:Fatty Acids; D008994:Monoacylglycerol Lipases