Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation

作者：Natividad R. Fuentes, Mohamed Mlih, Xiaoli Wang, Gabriella Webster, Sergio Cortes-Acosta, Michael L. Salinas, Ian R. Corbin, Jason Karpac, Robert S. Chapkin · 发表于：Journal of Lipid Research · 年份：2021 · DOI：10.1016/j.jlr.2021.100026 · 被引用次数：10 · 研究领域：Cancer, Lipids, and Metabolism、Cytokine Signaling Pathways and Interactions、PI3K/AKT/mTOR signaling in cancer

Epidermal growth factor receptor (EGFR) signaling drives the formation of many types of cancer, including colon cancer. Docosahexaenoic acid (DHA, 22∶6 Δ4,7,10,13,16,19 ), a chemoprotective long-chain n-3 polyunsaturated fatty acid suppresses EGFR signaling. However, the mechanism underlying this phenotype remains unclear. Therefore, we used super-resolution microscopy techniques to investigate the mechanistic link between EGFR function and DHA-induced alterations to plasma membrane nanodomains. Using isogenic in vitro (YAMC and IMCE mouse colonic cell lines) and in vivo ( Drosophila , wild type and Fat-1 mice) models, cellular DHA enrichment via therapeutic nanoparticle delivery, endogenous synthesis, or dietary supplementation reduced EGFR-mediated cell proliferation and downstream Ras/ERK signaling. Phospholipid incorporation of DHA reduced membrane rigidity and the size of EGFR nanoclusters. Similarly, pharmacological reduction of plasma membrane phosphatidic acid (PA), phosphatidylinositol-4,5-bisphosphate (PIP 2 ) or cholesterol was associated with a decrease in EGFR nanocluster size. Furthermore, in DHA-treated cells only the addition of cholesterol, unlike PA or PIP 2 , restored EGFR nanoscale clustering. These findings reveal that DHA reduces EGFR signaling in part by reshaping EGFR proteolipid nanodomains, supporting the feasibility of using membrane therapy, i.e., dietary/drug-related strategies to target plasma membrane organization, to reduce EGFR signaling and c...