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

Natividad R. Fuentes, Mohamed Mlih, Xiaoli Wang, Gabriella Webster, Sergio Cortes-Acosta, Michael L. Salinas, Ian R. Corbin, Jason Karpac, Robert S. Chapkin

Research output: Contribution to journalArticlepeer-review

Abstract

Epidermal growth factor receptor (EGFR) signaling drives the formation of many types of cancer, including colon cancer. Docosahexaenoic acid (DHA, 22:6Δ4,7,10,13,16,19), a chemoprotective long-chain n-3 polyunsaturated fatty acid suppresses EGFR signaling. However, the mechanism underlying this phenotype remains unclear. Therefore, we used superresolution microscopy techniques to investigate the mechanistic link between EGFR function and DHAinduced 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 EGFRmediated 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 (PIP2) or cholesterol was associated with a decrease in EGFR nanocluster size. Furthermore, in DHA-treated cells only the addition of cholesterol, unlike PA or PIP2, 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/drugrelated strategies to target plasma membrane organization, to reduce EGFR signaling and cancer risk.

Original languageEnglish (US)
Article number100026
JournalJournal of lipid research
Volume62
DOIs
StatePublished - 2021

Keywords

  • Cancer
  • Cholesterol
  • Membranes Fluidity
  • Omega-3 fatty acids
  • Receptors/Plasma membrane
  • Super-resolution microscopy

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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