Alteration of EGFR Spatiotemporal Dynamics Suppresses Signal Transduction

Abstract

The epidermal growth factor receptor (EGFR), which regulates cell growth and survival, is integral to colon tumorigenesis. Lipid rafts play a role in regulating EGFR signaling, and docosahexaenoic acid (DHA) is known to perturb membrane domain organization through changes in lipid rafts. Therefore, we investigated the mechanistic link between EGFR function and DHA. Membrane incorporation of DHA into immortalized colonocytes altered the lateral organization of EGFR. DHA additionally increased EGFR phosphorylation but paradoxically suppressed downstream signaling. Assessment of the EGFR-Ras-ERK1/2 signaling cascade identified Ras GTP binding as the locus of the DHA-induced disruption of signal transduction. DHA also antagonized EGFR signaling capacity by increasing receptor internalization and degradation. DHA suppressed cell proliferation in an EGFR-dependent manner, but cell proliferation could be partially rescued by expression of constitutively active Ras. Feeding chronically-inflamed, carcinogen-injected C57BL/6 mice a fish oil containing diet enriched in DHA recapitulated the effects on the EGFR signaling axis observed in cell culture and additionally suppressed tumor formation. We conclude that DHA-induced alteration in both the lateral and subcellular localization of EGFR culminates in the suppression of EGFR downstream signal transduction, which has implications for the molecular basis of colon cancer prevention by DHA.

Inhibitory effects of omega-3 fatty acids on injury-induced epidermal growth factor receptor transactivation contribute to delayed wound healing

“…1 and 2). This is consistent with our previous observations that DHA suppresses EGFR signal transduction (50). In contrast, in response to wounding, EPA and DHA reduced activation of PLC␥ 1 , Rac1, and Cdc42 (Figs.…”

“…1B). This is consistent with our previous observation that DHA reduces EGF-stimulated activation of ERK1/2 and STAT3 (50). In contrast, EPA treatment had no effect on EGF-stimulated PLC␥ 1 compared with control or LA-treated cells.…”

“…We previously showed that EGFR phosphorylation in response to direct stimulation with ligand is increased by DHA (50). However, other long-chain PUFA, including LA and EPA, did not recapitulate this same effect.…”

“…We previously demonstrated that a dietary long-chain n-3 PUFA, docosahexaenoic acid (DHA), suppresses EGFR signaling in mouse colonocytes (50). By altering the plasma membrane localization of EGFR, DHA increased receptor phosphorylation but paradoxically suppressed downstream activation of Ras, ERK1/2, and STAT3.…”

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

“…DHA is known to incorporate into biological membranes to alter membrane-domain organization and also to act as ligands of nuclear peroxisome proliferatoractivated receptors. 36,37 For these studies in vitro, researchers used o-3 FAs dissolved in bovine serum albumin-containing vehicle.…”