A novel role for n‐3 polyunsaturated fatty acids in inhibition of EGFR signal transduction

The epidermal growth factor receptor (EGFR), crucial for cell growth and survival, is a target for colon cancer treatment. EGFR signaling can be altered by disruption of lipid rafts. We investigated the mechanistic link between docosahexaenoic acid (DHA), EGFR function and localization, and cancer prevention. Chronically inflamed, carcinogen‐injected mice (n=12) were fed diets ± fish oil (enriched in DHA) for 18 wk. Colonic mucosa was analyzed by immunoblotting for phosphorylation (p‐) of EGFR and its downstream targets. Fish oil‐feeding induced >2‐fold (p<0.05) increase in p‐EGFR compared to corn oil (control) feeding. Paradoxically, downstream signaling was decreased, as indicated by reduced p‐STAT3 (50%) and p‐ERK 1/2 (30%). Immortalized mouse colonocytes (YAMC) were treated with fatty acids (50 μM) for 72 h, serum‐starved, and stimulated with EGF (25 ng/mL) for 10 min. DHA treatment increased p‐EGFR >2‐fold and receptor dimerization ~3‐fold with a concomitant decrease in p‐STAT3, p‐ERK1/2, and proliferation compared to control (no fatty acid) or linoleic acid treatment (p<0.05). Complementary membrane fractionation and confocal microscopy experiments indicated that DHA treatment reduced localization of EGFR in lipid rafts (p<0.05). We conclude that DHA elicits a novel suppression of EGFR signal transduction by altering the localization of the receptor within the plasma membrane. Grant Funding Source : NIH grant CA59034