One feature that distinguishes tumor cells from normal cells is their dysregulated metabolism. For example, tumor cells undergo glycolytic rather than oxidative metabolism, a change known as the Warburg effect, and they synthesize greater amounts of proteins and fatty acids than do normal cells (see the commentary by Yecies and Manning). Noting that these fatty acids must be released from lipid stores to be available to the tumor cell, Nomura et al. performed activity-based protein profiling of aggressive and nonaggressive human cancer cell lines to search for hydrolytic enzymes associated with malignancy. The authors found that monoacylgycerol lipase (MAGL), a serine hydrolase that degrades the endogenous cannabinoid 2-arachidonylglycerol and other MAGs, was enriched in the aggressive cell lines. MAGL was also more abundant in high-grade, human ovarian tumors than in benign tumors. Knockdown of MAGL in aggressive cancer cell lines by short hairpin RNA (shRNA) resulted in decreased amounts of free fatty acids (FFAs) and inhibited the migration, survival, and invasiveness of the cells, as assessed in vitro; conversely, lentiviral-mediated overexpression of MAGL in nonaggressive cancer cell lines had opposing effects. Transfer of an aggressive melanoma cell line containing MAGL-specific shRNA into immune-deficient mice resulted in smaller tumors than occurred when control shRNA-treated cells were used; however, the effect of knockdown of MAGL on tumor growth was reversed when the mice were fed a high-fat diet. Lipidomic analysis revealed the increased abundance of protumorigenic lipids, such as lysophosphatidic acid and prostaglandin E2, in aggressive cell lines, and blockade of the receptors for these lipids decreased the migration of these cell lines in vitro. Together, these data suggest that tumor cells use MAGL to generate a range of protumorigenic lipid signals that increase malignancy.
D. K. Nomura, J. Z. Long, S. Niessen, H. S. Hoover, S.-W. Ng, B. F. Cravatt, Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49–61 (2010). [Online Journal]
J. L. Yecies, B. D. Manning, Chewing the fat on tumor cell metabolism. Cell 140, 28–30 (2010). [Online Journal]