Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies

• Published in: PloS one Vol. 7; no. 8; p. e43468
• Main Authors: Preukschas, Michael, Hagel, Christian, Schulte, Alexander, Weber, Kristoffer, Lamszus, Katrin, Sievert, Henning, Pällmann, Nora, Bokemeyer, Carsten, Hauber, Joachim, Braig, Melanie, Balabanov, Stefan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.08.2012; Public Library of Science (PLoS)
• Subjects: Adult; Adults; Aged; Aged, 80 and over; Alkylating agents; Alkylation; Antineoplastic Agents, Alkylating - pharmacology; Apoptosis; Apoptosis - drug effects; Astrocytes; Biology; Biotechnology; Bone marrow; Brain; Brain cancer; Brain research; Brain tumors; Carmustine - pharmacology; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cellular Senescence - drug effects; Combined treatment; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Diagnosis; Dosage and administration; Enzymes; Eukaryotic Translation Initiation Factor 5A; Female; Forming; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Genetic aspects; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - enzymology; Glioblastoma - genetics; Glioblastoma - pathology; Glioma; Gliomas; Growth factors; Guanine - analogs & derivatives; Guanine - pharmacology; Health aspects; Hematology; Humans; Hydroxylase; Kinases; Lysine - analogs & derivatives; Lysine - biosynthesis; Male; Medical research; Medicine; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Molecular Targeted Therapy; Neoplasm Grading; Neurosurgery; Oncology; Ovarian cancer; Oxidoreductases Acting on CH-NH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-NH Group Donors - deficiency; Oxidoreductases Acting on CH-NH Group Donors - genetics; Oxidoreductases Acting on CH-NH Group Donors - metabolism; p53 Protein; Peptide Initiation Factors - deficiency; Peptide Initiation Factors - genetics; Pharmacology; Protein expression; Proteins; Reagents; Ribonucleic acid; RNA; RNA-Binding Proteins - genetics; Rodents; Senescence; Stem cells; Temozolomide; Tumor proteins; Tumors; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043468

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.