Cita:
High expression of a lipid-hydrolyzing enzyme in aggressive cancer generates free fatty acids and fuels oncogenic lipid-signaling pathways.
Monoglyceride lipase (MGLL; monoacylglycerol lipase; MAGL) regulates a fatty acid network that promotes cancer pathogenesis. Reproduced from Cell 140 (2010) doi:10.1016/j.cell.2009.11.027, with permission from Elsevier.
Malignancy in cancer correlates with altered metabolism, which supplies the energy and building blocks required for rapid growth. One dysregulated pathway, elevated lipogenesis, is thought to promote pathology by providing fatty acids for energy production, membrane lipids for growth and migration, and signaling lipids that trigger pro-tumorigenic cascades. However, newly synthesized fatty acids are quickly incorporated into lipid stores, leaving it unclear how heightened synthesis translates into available lipids for cellular functions. Now Benjamin Cravatt and colleagues show that the activity of monoglyceride lipase (MGLL) is increased in aggressive cancer, providing the principal source of free fatty acids (FFAs) and increasing production of bioactive lipids. The study, published in Cell, identifies MGLL as a potential target for cancer therapy, and suggests how a high-fat diet promotes malignancy.
MGLL cleaves monoacylglycerol species (MG) to liberate FFAs and glycerol during the sequential hydrolysis of triglycerides stored in adipose tissue. It also hydrolyzes the bioactive MG 2-arachidonoylglycerol (2-AG; 20:4 MG) in the brain, but it does not have any established role in cancer and does not control the levels of FFAs in normal tissues. Probing serine hydrolase activities across a panel of cell lines, the authors found that MGLL activity is consistently increased in cells derived from aggressive tumors. Higher basal levels of FFAs were eliminated by inhibition of the enzyme, indicating that it is the principal regulator of FFA levels in these cells.
Inhibition of MGLL increased MG, and decreased FFA levels, but the magnitude of these changes only matched for C20:4 species. This suggested that 16- and 18-carbon FFA species generated by MGLL are converted to alternative metabolites, a premise supported by lipidomic analysis revealing proportionate increases in corresponding lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) species.
To investigate the effect of MGLL expression on cancer pathogenicity, the authors stably blocked its expression in the malignant cells, and overexpressed it in non-aggressive lines. Growth, survival and migration of the cells were all promoted by MGLL expression, as was the growth of xenograft transplant tumors in immune-deficient mice. The impaired pathogenicity of MGLL-disrupted cells was rescued by treatment with exogenous C16:0 and C18:0 fatty acids, and a high-fat diet had the same effect on the growth of MGLL-disrupted tumors in mice.
To find out which lipid networks are modulated by the increase in FFAs, the authors conducted targeted lipidomics and identified a common profile of lipid metabolites regulated by MGLL. These included LPA and prostaglandin E2, treatment with either of which rescued the impaired migration of MGLL-disrupted cells.
These data show that MGLL–FFA regulates a lipid network in aggressive cancer cells, and demonstrates how increased lipogenesis can be paired with lipolysis to promote malignancy. Pharmacological inhibition of MGLL might be a viable cancer therapy. Furthermore, the ability of the high-fat diet to compensate for disrupted MGLL activity suggests that dietary fat might promote malignancy by mimicking the effects of increased MGLL expression.
Se comenta como la grasa alimentaria podría empeorar la malignidad de los tumores.
Cita:
El cáncer es una de las principales causas de muerte en los países occidentales. Entre los factores que contribuyen a la aparición de esta enfermedad, la dieta tiene un papel fundamental, y concretamente, las grasas son el principal componente relacionado con el incremento en la incidencia de la enfermedad cancerosa; sobre todo con el cáncer de mama, colorrectal, y prostático. De los lípidos de la dieta, se ha estudiado mucho el efecto beneficioso que tiene el aceite de pescado, rico en ácidos grasos poliinsaturados de la serie n-3, así como el aceite de oliva, rico en ácidos grasos monoinsaturados -principalmente ácido oleico-. Sin embargo, se ha descrito un efecto negativo por parte de los ácidos grasos de la serie n-6 y de las grasas saturadas. La nutrición constituye un aspecto importante en la vida del paciente canceroso; actualmente, se diseñan fórmulas nutricionales suplementadas con ácidos grasos poliinsaturados de la serie n-3, y otros componentes, como la arginina, ARN, lisina, etc., con el fin de paliar los efectos derivados de esta patología. Los resultados demuestran el descenso en la morbilidad, y por tanto, aumento de la calidad de vida, un descenso de la mortalidad, y una disminución en los costes relacionados.
Y obviamente como estos muchos artículos.