The long chain omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and its metabolite docosahexaenoic acid (DHA), inhibit cancer formation in vivo but their mechanism of action is unclear. ERK1/2 activation and inhibition have both been associated with the induction of tumor cell apoptosis by n-3 PUFAs.

We show here that low doses of EPA, in particular, inhibited the growth of pre-malignant and malignant keratinocytes more than their normal counterparts by a combination of cell cycle arrest and apoptosis. The growth inhibition of the oral squamous cell carcinoma (SCC) lines but not normal keratinocytes, by both n-3 PUFAs was associated with epidermal growth factor receptor (EGFR) autophosphorylation, a sustained phosphorylation of ERK1/2 and its downstream target p90RSK but not with phosphorylation of the PI3 kinase target Akt. Inhibition of EGFR with either the EGFR kinase inhibitor AG1478, or an EGFR blocking antibody, inhibited ERK1/2 phosphorylation and the blocking antibody partially antagonized growth inhibition by EPA, but not by DHA. DHA generated more reactive oxygen species and activated more JNK than EPA, potentially explaining its increased toxicity to normal keratinocytes.

Our results show that, in part, EPA specifically inhibits SCC growth and development by creating a sustained signaling imbalance to amplify the EGFR/ERK/p90RSK pathway in neoplastic keratinocytes to a supra-optimal level, supporting the chemopreventative potential of EPA, whose toxicity to normal cells might be reduced further by blocking its metabolism to DHA. Furthermore, ERK1/2 phosphorylation may have potential as a biomarker of n-3 PUFA function in vivo.