DHA alters lipid raft organization and cholesterol metabolism in cancer cells

Omega-3 fatty acids (ω3-FA), such as docosahaesanoic acid (DHA), were shown to attenuate growth and induce apoptosis in a variety of cancer cell lines derived from colonic, pancreatic, prostate, and breast cancers. In addition, recent findings indicate that ω3-FA act synergistically with chemotherapeutic agents and may be used to enhance radiosensitivity. However, the mechanism by which ω-3 PUFA inhibit cancer cells growth, is not yet well understood. 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 incorporation of ω3-FA alters the profile of lipid composition influencing EGFR downstream signal transduction in breast cancer cells. We demonstrate, by HPLC-GC analysis, that DHA is incorporated and metabolized in breast cancer plasma membrane, especially in lipid rafts, with different specificity for the phospholipids moiety, altering their structure. Of note is the observation that only the treatment with DHA, compared with other PUFA, reduces lipid raft cholesterol and sphingomyelin content, indicating a possible change in raft organization. Furthermore DHA exposure modifies cholesterol synthesis, reducing farnesyl or geranyl moiety. Many acylated proteins directly interact with plasma membrane, especially lipid rafts, by their saturated moieties. Membrane incorporation of DHA induces alterations in the lateral localization of EGFR and a decrease of EGFR downstream signal transduction. In particular, DHA induces down-regulation in the EGFR-Ras-ERK1/2 and PI3K pathways .