MAGL Contributes to Aggressiveness in Cancer

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Despite a growing understanding that the conversion of normal cells into cancerous cells is accompanied by metabolic changes, it remains unclear whether many of these changes play crucial roles in malignancy and disease progression. Increased lipid synthesis by fatty acid synthase has been suggested to contribute to cancer growth through both metabolic and signalling pathways. Researchers at the Scripps Institute reasoned that increased lipid synthesis must be accompanied by a lipolytic pathway to liberate stored fatty acids and have now shown that levels of monoacylglycerol lipase (MAGL) are highly elevated in aggressive cancer cells compared with less aggressive cancer cells and that this lipase, through hydrolysis of monoacylglycerols (MAGs), controls free fatty acid (FFA) levels in cancer cells.

JZL184 structure

JZL184

The resulting MAGL-FFA pathway promotes migration, survival, and in vivo tumour growth. Aggressive cancer cells thus partner lipogenesis with high lipolytic activity to generate an array of pro-tumorigenic signals that support their malignant behaviour. Treatment with the selective MAGL inhibitor, JZL184, significantly reduced FFA levels in aggressive cancer cells, a finding that contrasts with the function of MAGL in normal tissues, where the enzyme does not generally control FFA levels. Knock down of MAGL activity using shRNA probes in aggressive melanoma, ovarian and breast cancer cells reduced MAGL activity by 70%–80%, with corresponding elevations in MAGs and reductions in FFAs. shMAGL cancer cell lines showed reduced in vitro migration, invasion and survival under serum starvation conditions. Treatment with JZL184 also reduced cancer cell migration, but not survival, perhaps indicating that maximal effects on aggressiveness need sustained inhibition of MAGL. shMAGL cancer cells also showed markedly reduced tumour growth rates in subcutaneous xenograft transplantation studies performed in immune-deficient mice.

Daily treatment of mice bearing MAGL-expressing tumours with JZL184 (40 mg/kg po) produced similar impairments in tumour growth rates. Addition of palmitic or stearic acid, two principal FFAs regulated by MAGL in aggressive cancer cells, to cells with genetically or pharmacologically reduced levels of MAGL restored their migratory activity in vitro. Similarly, tumour growth was enhanced in MAGL-deficient xenografts when the mice were fed a high fat diet. Cancer cells engineered to stably over-express MAGL also showed significantly reduced MAGs and elevated FFAs, a profile that was accompanied by increased migration, invasion and survival in vitro and enhanced tumour growth in vivo.

The effects of MAGL on cancer aggressiveness were found not to be mediated by endocannabinoid signalling but are suggested instead to be, at least in part, caused by increased production of bioactive lipids such as LPA and PGE2 that act on GPCRs to promote high migratory activity.

Both in vitro and in vivo studies showed that aggressive cancer cells acquire the ability to liberate FFAs by increased expression of MAGL and that this contributes to the aggressive phenotype. Since MAGL is not required for cell survival, but instead promotes progression to a more aggressive phenotype, if shown to slow tumour progression in people, inhibitors of MAGL may have a better safety profile and offer advantages over existing treatments for cancer.

The study is published in the journal Cell.


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