(n-3) PUFA Alter Raft Lipid Composition and Decrease Epidermal Growth Factor Receptor Levels in Lipid Rafts of Human Breast Cancer Cells1,2

Abstract

To determine the mechanism by which the (n-3) fatty acids (FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease proliferation and induce apoptosis in MDA-MB-231 human breast cancer cells, we examined the effects of EPA and DHA on the lipid composition of lipid rafts as well as epidermal growth factor receptor (EGFR) raft localization and phosphorylation. (n-3) FA (a combination of EPA and DHA) inhibited (P < 0.05) the growth of MDA-MB-231 cells by 48-62% in the presence and absence, respectively, of linoleic acid (LA). More EPA and DHA were incorporated into lipid rafts isolated from MDA-MB-231 cells after treatment with (n-3) FA compared with cells treated with LA (P < 0.05). EPA and DHA treatment decreased (P < 0.05) lipid raft sphingomyelin, cholesterol, and diacylglycerol content and, in the absence of LA, EPA and DHA increased (P < 0.05) raft ceramide levels. Furthermore, there was a marked decrease in EGFR levels in lipid rafts, accompanied by increases in the phosphorylation of both EGFR and p38 mitogen-activated protein kinase (MAPK), in EPA+DHA-treated cells (P < 0.05). As sustained activation of the EGFR and p38 MAPK has been associated with apoptosis in human breast cancer cells, our results indicate that (n-3) FA modify the lipid composition of membrane rafts and alter EGFR signaling in a way that decreases the growth of breast tumors.

Omega-3 Polyunsaturated Fatty Acids Down-Modulate CXCR4 Expression and Function in MDA-MB-231 Breast Cancer Cells

“…The focus of this article is on the CXCR4-CXCL12 axis. The similar structures and functions of the other chemokine receptors, coupled with the fact that other cell surface molecules such as endothelial growth factor receptor and interleukin-2 receptor are displaced by n-3 PUFA treatment (29,30), suggest that other surface molecules that support migration may be affected in the same manner. This would be particularly true for molecules that require the lipid raft domains for signaling.…”

Docosahexaenoic acid inhibits the invasion of MDA-MB-231 breast cancer cells through upregulation of cytokeratin-1

“…For example, the urokinase-type plasminogen activator (uPA) and metalloproteinases (MMPs) are involved in extracellular matrix disorganization leading to the release of angiogenic factors such as Vegf or fgf, allowing the sprouting of new blood vessels and ultimately extra-and intravasation (13)(14)(15). Several studies have shown that lipid rafts in the plasma membrane can play an important role in cancer cells when n-3 Pufas were added, as it altered the cholesterol levels and consequently cell migration, invasion and angiogenesis (16,17). the DHa-induced decrease in breast cancer cell invasion may also be due to inhibition of voltage-gated na + channels (18,19).…”

The Beneficial Effects of Nutritional Compounds on Breast Cancer Metastasis

“…Incorporation of DHA or EPA into the cellular plasma membrane results in alterations of signaling patterns (Shaikh et al, 2004). The conformational changes induced in the plasma membrane also render certain surface receptors inaccessible to the ligand (Li et al, 2005;Schley et al, 2007). Additionally, DHA and EPA inhibit metastasis of MDA-MB-231 xenographs in mice to bone through targeting of CD44, the another prometastatic surface molecule (Mandal et al, 2010).…”