THE TUMOR SUPPRESSIVE ROLE OF MONOGLYCERIDE LIPASE IN LUNG CANCER

Abstract

Monoglyceride lipase (MGL) is a serine hydrolase that hydrolyzes 2-monoglycerides and produces fatty acid and glycerol. Our previous studies showed that there was MGL deficiency in the majority of human lung, breast, and colorectal cancer tissues as compared with normal tissues. Further studies suggested that MGL was a potential tumor-suppressor in the development of colorectal cancer. However, paradoxical findings about the role of MGL in tumorigenesis have been reported. It is therefore important to further elucidate the function of MGL in tumorigenesis. To that end, we generated MGL-knockout mouse and found that MGL knockout led to tumor formation in multiple organs/tissues of mice. Particularly, the major findings were lung adenocarcinomas. In cultured cells, MGL deletion enhanced cell proliferation and induced cellular transformation. Further molecular studies demonstrated that MGL suppressed EGFR signaling, NF-κB activity, and COX-2 expression. Deficiency of MGL may lead to over-activation of EGFR, NF-κB, and COX-2, and therefore contribute to tumorigenesis. We also found that MGL over-expression induced remarkable cancer cell apoptosis, and increased cleavage of caspase-8, caspase-9, caspase-3 and PARP. MGLinduced apoptosis thus involves both the intrinsic mitochondria-mediated and extrinsic death receptor-initiated apoptosis pathways. Most importantly, our data indicated that MGL interacted with a potent inhibitor of apoptosis, XIAP, and significantly reduced XIAP protein stability, which may unleash caspase-9 and caspase-3 from XIAP inhibition and thereby promote apoptosis. Some additional findings about MGL showed that MGL localization to lipid droplets was important for its regulation of cell growth and pro-tumorigenic signaling while MGL’s lipase activity is dispensable for these effects. We identified Asp-115 (D115) of MGL as the most important amino acid residue in mediating MGL localization to lipid droplets. We also found that MGL deficiency promotes lipid droplet formation and cellular lipid accumulation, which potentially promotes cancer cell survival under stressful conditions. Overall, our in vitro and in vivo data strongly support the notion that MGL is a tumor suppressor. The molecular findings about MGL may have revealed certain targets for personalized cancer therapy in the context of MGL deficiency and they also implicate potential roles of MGL in inflammation, immunity, and metabolism.