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    Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2. 
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    • Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2.
    •   QMRO Home
    • Blizard Institute
    • Centre for Neuroscience, Surgery and Trauma
    • Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2.
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    Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2.

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    Published version (3.134Mb)
    Volume
    34
    Pagination
    2716 - 2725
    DOI
    10.1093/carcin/bgt257
    Journal
    Carcinogenesis
    Issue
    12
    Metadata
    Show full item record
    Abstract
    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. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibition have both been associated with the induction of tumour cell apoptosis by n-3 PUFAs. We show here that low doses of EPA, in particular, inhibited the growth of premalignant and malignant keratinocytes more than the growth of 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 c-jun N-terminal kinase 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 signalling imbalance to amplify the EGFR/ERK/p90RSK pathway in neoplastic keratinocytes to a supraoptimal level, supporting the chemopreventive 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.
    Authors
    Nikolakopoulou, Z; Nteliopoulos, G; Michael-Titus, AT; Parkinson, EK
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/13810
    Collections
    • Centre for Neuroscience, Surgery and Trauma [1115]
    Language
    eng
    Copyright statements
    © The Author 2013. Published by Oxford University Press.
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