Docosahexanoic acid influences 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. The mechanisms underlying the anti-tumour effects of ω3-FA are complex. Lipids are likely to be utilized for membrane composition, protein modification and signal transduction as a second messenger, all of which are crucial for cell survival, proliferation and transformation in cancer cells. 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 the treatment with DHA leads to accumulation of triglycerides and cholesteryl esters. 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 .