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

Michael Preukschas; Christian Hagel; Alexander Schulte; Kristoffer Weber; Katrin Lamszus; Henning Sievert; Nora Pällmann; Carsten Bokemeyer; Joachim Hauber; Melanie Braig; Stefan Balabanov

doi:10.1371/journal.pone.0043468

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

PLoS One. 2012;7(8):e43468. doi: 10.1371/journal.pone.0043468. Epub 2012 Aug 21.

Authors

Michael Preukschas¹, Christian Hagel, Alexander Schulte, Kristoffer Weber, Katrin Lamszus, Henning Sievert, Nora Pällmann, Carsten Bokemeyer, Joachim Hauber, Melanie Braig, Stefan Balabanov

Affiliation

¹ Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Alkylating / pharmacology
Apoptosis / drug effects
Carmustine / pharmacology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cellular Senescence / drug effects
Dacarbazine / analogs & derivatives
Dacarbazine / pharmacology
Eukaryotic Translation Initiation Factor 5A
Female
Gene Expression Regulation, Neoplastic* / drug effects
Gene Knockdown Techniques
Glioblastoma / drug therapy
Glioblastoma / enzymology
Glioblastoma / genetics*
Glioblastoma / pathology
Guanine / analogs & derivatives
Guanine / pharmacology
Humans
Lysine / analogs & derivatives*
Lysine / biosynthesis
Male
Mixed Function Oxygenases / genetics*
Mixed Function Oxygenases / metabolism
Molecular Targeted Therapy*
Neoplasm Grading
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
Peptide Initiation Factors / deficiency
Peptide Initiation Factors / genetics*
RNA-Binding Proteins / genetics*
Temozolomide

Substances

Antineoplastic Agents, Alkylating
N(1)-guanyl-1,7-diaminoheptane
Peptide Initiation Factors
RNA-Binding Proteins
hypusine
Guanine
Dacarbazine
Mixed Function Oxygenases
deoxyhypusine hydroxylase
Oxidoreductases Acting on CH-NH Group Donors
deoxyhypusine synthase
Lysine
Carmustine
Temozolomide

Grants and funding

These studies were supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (BA 3506/1-1 and HA 2580/4-1; www.dfg.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.