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Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death

Michael W. Ronellenfitsch, Daniel P. Brucker, Michael C. Burger, Stefan Wolking, Felix Tritschler, Johannes Rieger, Wolfgang Wick, Michael Weller, Joachim P. Steinbach
DOI: http://dx.doi.org/10.1093/brain/awp093 1509-1522 First published online: 5 May 2009

Summary

Although inhibition of the epidermal growth factor receptor is a plausible therapy for malignant gliomas that, in vitro, enhances apoptosis, the results of clinical trials have been disappointing. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates starvation signals and generates adaptive responses that aim at the maintenance of energy homeostasis. Antagonism of mTOR has been suggested as a strategy to augment the efficacy of epidermal growth factor receptor inhibition by interfering with deregulated signalling cascades downstream of Akt. Here we compared effects of antagonism of mTOR utilizing rapamycin or a small hairpin RNA-mediated gene silencing to those of epidermal growth factor receptor inhibition or combined inhibition of epidermal growth factor receptor and mTOR in human malignant glioma cells. In contrast to epidermal growth factor receptor inhibition, mTOR antagonism neither induced cell death nor enhanced apoptosis induced by CD95 ligand or chemotherapeutic drugs. However, mTOR inhibition mimicked the hypoxia-protective effects of epidermal growth factor receptor inhibition by maintaining adenosine triphosphate levels. These in vitro experiments thus challenge the current view of mTOR as a downstream target of Akt that mediates antiapoptotic stimuli. Under the conditions of the tumour microenvironment, metabolic effects of inhibition of epidermal growth factor receptor, Akt and mTOR may adversely affect outcome by protecting the hypoxic tumour cell fraction.

  • mTOR
  • EGFR
  • glioma
  • hypoxia
  • metabolism
  • Abbreviations:
    Abbreviations:
    4E-BP1
    eukaryotic translation initiation factor 4E binding protein 1
    CD95L
    CD95 ligand
    EGFR
    epidermal growth factor receptor
    eIF4E
    eukaryotic translation initiation factor 4E
    HIF-1 α
    hypoxia inducible factor-1 α
    LDH
    lactate dehydrogenase
    mTOR
    mammalian target of rapamycin
    p42/44 MAPK
    p42/44 mitogen-activated protein kinase
    PI3K
    phosphatidyl-inositole-3-phosphate kinase
    RPS6
    ribosomal protein S6
    S6K1
    ribosomal protein S6 kinase 1
    shRNA
    small hairpin RNA
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