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Brain Advance Access published online on May 4, 2009
Brain, doi:10.1093/brain/awp093
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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. Ronellenfitsch1,2, Daniel P. Brucker2, Michael C. Burger2, Stefan Wolking1, Felix Tritschler1, Johannes Rieger2, Wolfgang Wick3, Michael Weller1,4 and Joachim P. Steinbach2

1 Laboratory for Molecular Neurooncology, Department of General Neurology, University of Tübingen, Tübingen, Germany 2 Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital, Frankfurt am Main, Germany 3 German Cancer Research Centre, Heidelberg, Germany 4 Department of Neurology, University Hospital Zürich, Zürich, Switzerland

Correspondence to: J. P. Steinbach, Dr. Senckenberg Institute of Neurooncology, Centre of Neurology and Neurosurgery, Goethe-University Hospital, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. E-mail: joachim.steinbach{at}med.uni-frankfurt.de

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.

Key Words: mTOR; EGFR; glioma; hypoxia; metabolism

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 {alpha}, hypoxia inducible factor-1 {alpha}; 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

Received October 29, 2008. Revised March 9, 2009. Accepted March 10, 2009.


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