jzl-184 and Liver-Neoplasms

Monoacylglycerol lipase (MAGL) is a key enzyme in lipid metabolism that is demonstrated to be involved in tumor progression through both energy supply of fatty acid (FA) oxidation and enhancing cancer cell malignance. The aim of this study was to investigate whether MAGL could be a potential therapeutic target and prognostic indicator for hepatocellular carcinoma (HCC). To evaluate the relationship between MAGL levels and clinical characteristics, a tissue microarray (TMA) of 353 human HCC samples was performed. MAGL levels in HCC samples were closely linked to the degree of malignancy and patient prognosis. RNA interference, specific pharmacological inhibitor JZL-184 and gene knock-in of MAGL were utilized to investigate the effects of MAGL on HCC cell proliferation, apoptosis, and invasion. MAGL played important roles in both proliferation and invasion of HCC cells through mechanisms that involved prostaglandin E2 (PGE2) and lysophosphatidic acid (LPA). JZL-184 administration significantly inhibited tumor growth in mice. Furthermore, we confirmed that promoter methylation of large tumor suppressor kinase 1 (LATS1) resulted in dysfunction of the Hippo signal pathway, which induced overexpression of MAGL in HCC. These results indicate that MAGL could be a potentially novel therapeutic target and prognostic indicator for HCC.

Topics: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Benzodioxoles; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Disease Progression; DNA Methylation; Enzyme Inhibitors; Female; Hep G2 Cells; Hippo Signaling Pathway; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Monoacylglycerol Lipases; Neoplasm Invasiveness; Piperidines; Prognosis; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; RNA Interference; Signal Transduction