| Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. | |
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MedLine Citation:
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PMID: 14996711 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Epidermal growth factor receptor (EGFR) signaling has become an important target for drug development because EGFR signaling enhances tumor cell proliferation, migration, and invasion and inhibits apoptosis. However, the results of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing. Here, we report a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hypoxia, which contrasts with their proapoptotic effects under normoxia. Under hypoxic conditions, both agents reduced glucose consumption, delayed ATP depletion, and preserved the mitochondrial membrane potential. Exposure either to hypoxia or the EGFR inhibitors under normoxic conditions resulted in the dephosphorylation of ribosomal protein S6, a player in the energy and nutrient-sensing pathway governed by mammalian target-of-rapamycin (mTOR). Combined inhibition of phosphatidylinositol 3'-kinase (PI3K) and extracellular signal-regulated kinase-1/2 (ERK1/2) mimicked the protective effects of EGFR inhibition on hypoxia-induced cell death and protein S6 dephosphorylation. These results caution that therapies targeting EGFR signaling pathways can protect tumor cells from acute hypoxia. |
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Authors:
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Joachim P Steinbach; Andrea Klumpp; Hartwig Wolburg; Michael Weller |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Cancer research Volume: 64 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2004 Mar |
Date Detail:
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Created Date: 2004-03-03 Completed Date: 2004-03-31 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 1575-8 Citation Subset: IM |
Affiliation:
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Department of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, School of Medicine, Tübingen, Germany. joachim.steinbach@uni-tuebingen.de |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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antagonists & inhibitors Adenosine Triphosphate / metabolism Cell Death / drug effects Cell Hypoxia* DNA Replication / drug effects Glioma / drug therapy, pathology* Glucose / metabolism Humans Membrane Potentials / drug effects Mitochondria / drug effects, physiology Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases / antagonists & inhibitors Receptor, Epidermal Growth Factor / antagonists & inhibitors* Signal Transduction / drug effects* Tyrphostins / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Tyrphostins; 170449-18-0/tyrphostin AG 1478; 50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 2.7.11.24/Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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