Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis

By Daniel K. Nomura, Jonathan Z. Long, Sherry L. Niessen, Heather S. Hoover, S. Ng, B. Cravatt. Cell, 2010

943 citations recorded by the source corpus.

Tumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer pathogenesis, however, remains unknown. Here, we show that the enzyme monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in non-aggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity -- phenotypes that are reversed by an MAGL inhibitor. Interestingly, impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of pro-tumorigenic signals.

Subfields: Biochemistry, Cancer Research, Pharmacology

View Paper: https://www.semanticscholar.org/paper/4e5efbe66bee409401e408d66a0d1276ec14a249

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. T. Walther
2. Robert V Farese
3. Craig B. Thompson
4. Joshua D. Rabinowitz
5. R. Zechner
6. M. V. Vander Heiden
7. A. Schulze
8. B. Spiegelman

In Cancer Research

1. M. V. Vander Heiden
2. Craig B. Thompson
3. E. White
4. Joshua D. Rabinowitz
5. A. Schulze
6. B. Spiegelman
7. Adrian L. Harris
8. E. Lengyel

In Pharmacology

1. Craig B. Thompson
2. Robin Mathew
3. E. White

Citations in the corpus

• Morbidity and mortality associated with obesity. (2017, background): “Obesity increases cancer incidence (73) partly by converting high-fat diet supplied fatty acids or de novo synthesized fatty acids into protumorigenic signaling lipids.”
• Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development (2013, background): “A recent study identified a specific lipid signature that was associated with overexpression of monoglyceride-lipase (MAGL), a lipase involved in releasing FFAs from TAGs (Nomura et al., 2010).”
• Membrane Lipid Composition: Effect on Membrane and Organelle Structure, Function and Compartmentalization and Therapeutic Avenues (2019, background): “In addition, other findings suggest that dietary-derived lipids might enlarge the overall lipid composition of malignant cells and so influence multiple signaling events within tumors [151].”
• Targeting cancer metabolism: a therapeutic window opens (2011, background): “Lipids also have important signalling functions in cells, and chemical genetic screens have identified lipases that release fatty acyl chains from glycerol as therapeutic targets in some cancer”
• Molecular mechanisms of cancer development in obesity (2011, background): “This pathway is upregulated in certain aggressive cancer”
• Cholesteryl Ester Accumulation Induced by PTEN Loss and PI3K/AKT Activation Underlies Human Prostate Cancer Aggressiveness (2014, background): “In parallel with lipogenesis, lipolysis has also been shown to be elevated in multiple human cancers (Nomura et al., 2010).”
• Adipose tissue and adipocytes supports tumorigenesis and metastasis (2013, background): “Aggressive epithelial tumor cell lines and primary tumors reportedly overexpress MAGL which contributes to the production of pro-tumorigenic fatty acid products [30].”
• Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids (2013, background): “Intriguingly, the enzyme MG lipase (MAGL), which generates free fatty acids from monoacylglycerols, is highly expressed in aggressive cancer cells and its over-expression enhances tumorigenicity (26).”
• Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. (2014, background): “A recent study also demonstrated that monoacylglycerol lipase (MAGL) drives tumorigenesis through the lipolytic release and remodeling of free FAs, and that exogenous sources of FAs can contribute to malignancy in cancers lacking MAGL activity (Nomura et al., 2010).”
• Cellular Fatty Acid Metabolism and Cancer (2013, background): “While sphingolipid metabolism is not a focus of this review, it is noteworthy that specific sphingolipids, such as ceramides and sphingosine-1-phosphate, are bioactive signaling molecules that generally suppress or promote tumors, respectively (Ogretmen and Hannun, 2004).”