The Monoacylglycerol Lipase Inhibitor JZL184 Inhibits Lung Cancer Cell Invasion and Metastasis via the CB1 Cannabinoid Receptor
Jan Lukas Prüser, Robert Ramer, Felix Wittig, Igor Ivanov, Jutta Merkord, Burkhard Hinz
Abstract
Abstract A targeted modulation of the endocannabinoid system is currently discussed as a promising strategy for cancer treatment. An important enzyme for the endocannabinoid metabolism is the monoacylglycerol lipase (MAGL), which catalyzes the degradation of 2-arachidonoylglycerol (2-AG) to glycerol and free fatty acids. In this study, we investigated the influence of MAGL inhibition on lung cancer cell invasion and metastasis. Using LC-MS, significantly increased 2-AG levels were detected in A549 cells treated with the MAGL inhibitor JZL184. In athymic nude mice, JZL184 suppressed metastasis of A549 cells in a dose-dependent manner, whereby the antimetastatic effect was cancelled by the CB1 receptor antagonist AM-251. In vitro, JZL184 induced a time- and concentration-dependent reduction of A549 cell invasion through Matrigel-coated membranes, which was likewise reversed by AM-251. An MAGL inhibition–associated reduction of free fatty acids as a cause of the anti-invasive effect could be excluded by add-back experiments with palmitic acid. Both JZL184 and the MAGL substrate 2-AG led to an increased formation of the tissue inhibitor of metalloproteinase-1 (TIMP-1), whereby a TIMP-1 knockdown using siRNA significantly attenuated the anti-invasive effects of both substances. Decreased invasion and TIMP-1 upregulation was also caused by the MAGL inhibitors JW651 and MJN110 or transfection with MAGL siRNA. A CB1- and TIMP-1–dependent anti-invasive effect was further confirmed for JZL184 in H358 lung cancer cells. In conclusion, MAGL inhibition led to a CB1-dependent decrease in human lung cancer cell invasion and metastasis via inhibition of 2-AG degradation, with TIMP-1 identified as a mediator of the anti-invasive effect.