Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies
| Autor: | Carsten Bokemeyer, Christian Hagel, Melanie Braig, Stefan Balabanov, Kristoffer Weber, Alexander Schulte, Joachim Hauber, Nora Pällmann, Henning Sievert, Katrin Lamszus, Michael Preukschas |
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| Přispěvatelé: | University of Zurich, Balabanov, S |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Cell cycle checkpoint Cancer Treatment lcsh:Medicine Apoptosis Mixed Function Oxygenases Small hairpin RNA chemistry.chemical_compound Peptide Initiation Factors Eukaryotic initiation factor Molecular Cell Biology Deoxyhypusine synthase Signaling in Cellular Processes Molecular Targeted Therapy lcsh:Science Neurological Tumors Cellular Senescence Aged 80 and over Oxidoreductases Acting on CH-NH Group Donors Multidisciplinary biology Cell Cycle RNA-Binding Proteins Deoxyhypusine Hydroxylase Signaling in Selected Disciplines Dacarbazine Gene Expression Regulation Neoplastic Oncology Gene Knockdown Techniques Medicine Female Research Article Signal Transduction Adult Guanine 610 Medicine & health 1100 General Agricultural and Biological Sciences 1300 General Biochemistry Genetics and Molecular Biology Glioma Cell Line Tumor medicine Temozolomide Humans Biology Antineoplastic Agents Alkylating Aged Cell Proliferation Hypusine Oncogenic Signaling 1000 Multidisciplinary Cell growth Lysine lcsh:R Cancers and Neoplasms Chemotherapy and Drug Treatment medicine.disease Molecular biology Carmustine chemistry 10032 Clinic for Oncology and Hematology biology.protein Cancer research lcsh:Q Transcriptional Signaling Neoplasm Grading Glioblastoma Glioblastoma Multiforme |
| Zdroj: | PLoS ONE, Vol 7, Iss 8, p e43468 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Glioblastomas are highly aggressive brain tumors of adults with poor clinical outcome. Despite a broad range of new and more specific treatment strategies, therapy of glioblastomas remains challenging and tumors relapse in all cases. Recent work demonstrated that the posttranslational hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is a crucial regulator of cell proliferation, differentiation and an important factor in tumor formation, progression and maintenance. Here we report that eIF-5A as well as the hypusine-forming enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are highly overexpressed in glioblastoma patient samples. Importantly, targeting eIF-5A and its hypusine modification with GC7, a specific DHS-inhibitor, showed a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes were not affected. Furthermore, we identified p53 dependent premature senescence, a permanent cell cycle arrest, as the primary outcome in U87-MG cells after treatment with GC7. Strikingly, combined treatment with clinically relevant alkylating agents and GC7 had an additive antiproliferative effect in glioblastoma cell lines. In addition, stable knockdown of eIF-5A and DHS by short hairpin RNA (shRNA) could mimic the antiproliferative effects of GC7. These findings suggest that pharmacological inhibition of eIF-5A may represent a novel concept to treat glioblastomas and may help to substantially improve the clinical course of this tumor entity. |
| Databáze: | OpenAIRE |
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