Heightened lipogenesis is an established early hallmark of dysregulated metabolism and pathogenicity in cancer (Menendez and Lupu, 2007
). Cancer lipogenesis appears to be driven principally by FAS, which is elevated in most transformed cells and important for survival and proliferation (De Schrijver et al., 2003
; Kuhajda et al., 2000
; Vazquez-Martin et al., 2008
). It is not yet clear how FAS supports cancer growth, but most of the proposed mechanisms invoke pro-tumorigenic functions for the enzyme s fatty acid products and their lipid derivatives (Menendez and Lupu, 2007
). This creates a conundrum, since the fatty acid molecules produced by FAS are thought to be rapidly incorporated into neutral- and phospho-lipids, pointing to the need for complementary lipolytic pathways in cancer cells to release stored fatty acids for metabolic and signaling purposes (Prentki and Madiraju, 2008
; Przybytkowski et al., 2007
). Consistent with this hypothesis, we found that acute treatment with the FAS inhibitor C75 (40 μM, 4 h) did not reduce FFA levels in cancer cells (data not shown). Furthermore, aggressive and non-aggressive cancer cells exhibited similar levels of FAS (data not shown), indicating that lipogenesis in the absence of paired lipolysis may be insufficient to confer high levels of malignancy.
Here we show that aggressive cancer cells do indeed acquire the ability to liberate FFAs from neutral lipid stores as a consequence of heightened expression of MAGL. MAGL and its FFA products were found to be elevated in aggressive human cancer cell lines from multiple tissues of origin, as well as in high-grade primary human ovarian tumors. These data suggest that the MAGL-FFA pathway may be a conserved feature of advanced forms of many types of cancer. Further evidence in support of this premise originates from gene expression profiling studies, which have identified increased levels of MAGL in primary human ductal breast tumors compared to less malignant medullary breast tumors (Gjerstorff et al., 2006
). The key role that MAGL plays in regulating FFA levels in aggressive cancer cells contrasts with the function of this enzyme in normal tissues, where it mainly controls the levels of MAGs, but not FFAs (Long et al., 2009b
). These data thus provide a striking example of the co-opting of an enzyme by cancer cells to serve a distinct metabolic purpose that supports their pathogenic behavior.
We determined that MAGL is both necessary and sufficient to elevate FFAs and confer high migratory and tumorigenic activity in cancer cells. Blockade of MAGL impaired not only in vitro migration, but also in vivo tumor growth, and both phenotypes were rescued by exogenous sources of FFAs. These data, in combination with the lack of effect of cannnabinoid receptor antagonists on migration, indicate that the mechanism of MAGL-stimulated cancer aggressiveness involves the action of FFA-derived products, rather than reductions in MAGL substrates, such as the endocannabinoid 2-AG. Additional studies argued against a major role for β-oxidation or glycolysis in mediating MAGL-dependent aggressiveness. Instead, we found that MAGL regulates a host of secondary lipid metabolites that include key signaling molecules, such as LPA and PGE2
, known to support cancer malignancy. Our finding that impairments in the MAGL–FFA pathway can be rescued by exogenous fatty acids, including a high-fat diet in vivo, has provocative implications for the crosstalk between obesity and tumorigenesis. It has been postulated that excessive fat accumulation may exacerbate the development and progression of cancer (Calle and Kaaks, 2004
; Calle et al., 2003
), and, conversely, reductions in caloric intake have been shown to impede tumor growth (Kalaany and Sabatini, 2009
). Our data suggest one mechanism whereby a high-fat diet might promote malignancy, namely, by stimulating the growth and migratory activity of cancer cells that do not themselves exhibit high rates of lipolysis.
Taken together, our results indicate that MAGL serves as key metabolic hub in aggressive cancer cells, where the enzyme regulates a fatty acid network that feeds into a number of pro-tumorigenic signaling pathways. Additional studies will be required to determine precisely how FFAs are converted to pro-tumorigenic lipid transmitters, although some obvious candidate pathways can be schematized (). It will be interesting to determine whether any of the enzymatic components of these pathways are also dysregulated in pathogenic cancers. One might also anticipate that cancer cells could exhibit heightened levels of additional hydrolytic activities (e.g., di- and tri-acylglycerol hydrolysis) to further capitalize on their lipogenic state, although we should note that the aggressive cancer cells examined herein displayed much lower di- and tri-acylglycerol lipase activity compared to MAGL activity, and these former activities did not differ between aggressive and non-aggressive cancer cells (Figure S1
). Finally, considering that endocannabinoids (Wang et al., 2008
), β-oxidation (Buzzai et al., 2005
; Liu, 2006
), and fatty acid-sustained glycolysis (Przybytkowski et al., 2007
) have each been described as potential contributing elements to tumorigenesis, it is possible that these pathways may prove relevant for MAGL-dependent aggressiveness in other types of cancer. Independent of which of these mechanisms is operational in specific cancers, our data suggest that they would each function downstream of MAGL, thus designating this enzyme as a potentially exciting pharmacological target for future cancer therapy.