TY - JOUR
T1 - Membrane therapy using dha suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation
AU - Fuentes, Natividad R.
AU - Mlih, Mohamed
AU - Wang, Xiaoli
AU - Webster, Gabriella
AU - Cortes-Acosta, Sergio
AU - Salinas, Michael L.
AU - Corbin, Ian R.
AU - Karpac, Jason
AU - Chapkin, Robert S.
N1 - Publisher Copyright:
© 2021 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Cancer
KW - Cholesterol
KW - Membranes Fluidity
KW - Omega-3 fatty acids
KW - Receptors/Plasma membrane
KW - Super-resolution microscopy
UR - http://www.scopus.com/inward/record.url?scp=85103668709&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103668709&partnerID=8YFLogxK
U2 - 10.1016/J.JLR.2021.100026
DO - 10.1016/J.JLR.2021.100026
M3 - Article
C2 - 33515553
AN - SCOPUS:85103668709
SN - 0022-2275
VL - 62
JO - Journal of lipid research
JF - Journal of lipid research
M1 - 100026
ER -