DHA modifies lipid raft structure and function of cancer cells

In vivo and in vitro studies suggest that ω-3 PUFA can be cancer chemopreventive, chemosuppressive and auxiliary agents for cancer therapy. Ω-3 PUFA could alter cancer growth influencing cell replication, cell cycle, and cell death. The mechanisms of PUFA action are still unclear. It was suggested that these fatty acids might change the fluidity and structure of cell membrane, especially of lipid rafts. In fact the possible dismantling of lipid rafts is particularly important in cancer therapy. We propose that DHA alters raft structure which influences receptor function and signal transduction in human breast cancer adenocarcinoma MDA-MB-231 cells, estrogen-insensible and over-expressing EGF receptor. We have isolated lipid rafts as Detergent Resistant Membranes (DRM) in presence of Triton X-100 by ultracentrifugation in sucrose gradient. Our data suggest that DHA is incorporated and metabolized in breast cancer membrane, especially in lipid rafts with different specificity for the phospholipids moiety, increasing ω-3 PUFA content and reducing ω-6 PUFA. It is worth noting that only the treatment with DHA, compared with other PUFA, reduces lipid raft cholesterol and sphingomyelin content. Moreover DHA induces a reduction of cholesterol synthesis and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) activity. Disruption of cholesterol-rich membrane microdomains by DHA exposure led to a spatial disorganization of EGFR in plasma membranes. In fact we have demonstrated that DHA induces the exclusion EGFR from DRM to Detergent Soluble Membranes with a decrease of Ras raft localization and consequently a modulation of ERK-PI3K pathway. In conclusion DHA incorporated into lipid rafts, induces the formation of “declustered rafts” with a reorganization of lipids and signal transduction proteins.