Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-24074
Ronellenfitsch, M W; Brucker, D P; Burger, M C; Wolking, S; Tritschler, F; Rieger, J; Wick, W; Weller, M; Steinbach, J P (2009). 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. Brain: A Journal of Neurology, 132(Pt 6):1509-1522.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology|
|DDC:||610 Medicine & health|
|Deposited On:||18 Nov 2009 14:14|
|Last Modified:||27 Nov 2013 19:04|
|Publisher:||Oxford University Press|
|Additional Information:||This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Brain : a Journal of Neurology following peer review. The definitive publisher-authenticated version DOI: 10.1093/brain/awp093|
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