Journal Article

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 and Joachim P. Steinbach

in Brain

Published on behalf of The Guarantors of Brain

Volume 132, issue 6, pages 1509-1522
Published in print June 2009 | ISSN: 0006-8950
Published online May 2009 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awp093
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

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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.

Keywords: mTOR; EGFR; glioma; hypoxia; metabolism

Journal Article.  8711 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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