Oxidative stress and cell death are enhanced by N-3 pufa membrane incorporation in breast cancer cells

Epidemiological studies highlight the correlation between the long chain n-3 polyunsaturated fatty acids (n-3 PUFAs) and a reduction of cancer, suggesting a protective n-3 PUFA effect. The n-3 PUFAs have been shown to improve the efficacy of various cancer prevention, chemotherapy drugs and radiation against cancer. The potential mechanism comprises mainly alterations of cellular lipid composition and metabolism, which might consequently modulate membrane properties and functions, eicosanoid productions, and modulation of different signaling pathways related to cell growth and death. The goal of the study was to investigate the effects of n-3 PUFA (EPA and DHA) incorporation in two lines of human breast cancer cells characterized by different expression of ER receptor. After treatments, PUFAs were partially metabolized from both cell lines and were incorporated in membrane phospholipids with different specificity, especially in lipid rafts. The n-3 PUFA incorporation increased the membrane unsaturation degree, decreased the sphingomyelin and cholesterol content, and altered the Glutathione Peroxidase (GPx), Reductase, Catalase activity, GSH and Malondialdehyde (MDA) content. By using the annexin-V staining we confirmed that DHA and EPA induce apoptosis and in addition we found that caspase-8, an effector caspase, is activated in n-3 PUFA treated cells. In conclusion we speculate that in breast cancer cells DHA and EPA incorporation alters membrane organization and might increase ROS accumulation in or near the plasma membrane especially lipid rafts where the assembly of the death inducing signaling complex (DISC) and the subsequent activation of apoptosis take place.