Nomura Daniel K, Lombardi Donald P, Chang Jae Won, Niessen Sherry, Ward Anna M, Long Jonathan Z, Hoover Heather H, Cravatt Benjamin F
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.
Chem Biol. 2011 Jul 29;18(7):846-56. doi: 10.1016/j.chembiol.2011.05.009.
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.
癌细胞将增强的脂肪生成与脂肪分解相结合，以产生支持恶性肿瘤的脂肪酸网络。单酰甘油脂肪酶（MAGL）在此过程中发挥主要作用，它将单甘油酯（包括内源性大麻素2-花生四烯酸甘油酯（2-AG））转化为游离脂肪酸。在此，我们表明，与雄激素依赖性人前列腺癌细胞系相比，MAGL在雄激素非依赖性细胞系中表达升高，并且该酶的药理学或RNA干扰破坏会损害前列腺癌的侵袭性。用脂肪酸或大麻素受体-1（CB1）拮抗剂处理可部分逆转这些效应，而同时用这两种药物处理则可完全逆转。我们进一步表明，MAGL是与上皮-间质转化和癌细胞的干细胞样特性相关的基因特征的一部分，支持该酶在肿瘤发生代谢中的作用，对于前列腺癌而言，这涉及对内源性大麻素和脂肪酸途径的双重控制。
