Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

Sebastian K. -J. Landor, Anders P. Mutvei, Veronika Mamaeva, Shaobo Jin, Morten Busk, Ronald Borra, Tove J. Gronroos, Pauliina Kronqvist, Urban Lendahl, Cecilia Maria Sahlgren*

*Corresponding author voor dit werk

    OnderzoeksoutputAcademicpeer review

    103 Citaten (Scopus)

    Samenvatting

    A switch from oxidative phosphorylation to glycolysis is frequently observed in cancer cells and is linked to tumor growth and invasion, but the underpinning molecular mechanisms controlling the switch are poorly understood. In this report we show that Notch signaling is a key regulator of cellular metabolism. Both hyper- and hypoactivated Notch induce a glycolytic phenotype in breast tumor cells, although by distinct mechanisms: hyperactivated Notch signaling leads to increased glycolysis through activation of the phosphatidylinositol 3-kinase/AKT serine/threonine kinase pathway, whereas hypoactivated Notch signaling attenuates mitochondrial activity and induces glycolysis in a p53-dependent manner. Despite the fact that cells with both hyper- and hypoactivated Notch signaling showed enhanced glycolysis, only cells with hyperactivated Notch promoted aggressive tumor growth in a xenograft mouse model. This phenomenon may be explained by that only Notch-hyperactivated, but not -hypoactivated, cells retained the capacity to switch back to oxidative phosphorylation. In conclusion, our data reveal a role for Notch in cellular energy homeostasis, and show that Notch signaling is required for metabolic flexibility.

    Originele taal-2English
    Pagina's (van-tot)18814-18819
    Aantal pagina's6
    TijdschriftProceedings of the National Academy of Sciences of the United States of America
    Volume108
    Nummer van het tijdschrift46
    DOI's
    StatusPublished - 15-nov.-2011

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