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
| العنوان: | 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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| المؤلفون: | Michael Weller, Felix Tritschler, Michael C. Burger, Stefan Wolking, Joachim P. Steinbach, Johannes Rieger, Daniel P. Brucker, Michael W. Ronellenfitsch, Wolfgang Wick |
| المصدر: | Brain. 132:1509-1522 |
| بيانات النشر: | Oxford University Press (OUP), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Fas Ligand Protein, Adenosine Triphosphate, Growth factor receptor, Epidermal growth factor, Tumor Cells, Cultured, Humans, Growth factor receptor inhibitor, Gene Silencing, Epidermal growth factor receptor, Enzyme Inhibitors, Protein kinase B, PI3K/AKT/mTOR pathway, Membrane Potential, Mitochondrial, Sirolimus, Antibiotics, Antineoplastic, Cell Death, integumentary system, biology, TOR Serine-Threonine Kinases, RPTOR, Ribosomal Protein S6 Kinases, 70-kDa, Glioma, Cell Hypoxia, ErbB Receptors, Cancer research, biology.protein, Neurology (clinical), Signal transduction, Protein Kinases, Signal Transduction |
| الوصف: | 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. |
| تدمد: | 1460-2156 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a597bc2a3fe32c09581a0420b15c3435Test https://doi.org/10.1093/brain/awp093Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a597bc2a3fe32c09581a0420b15c3435 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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