title: Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies.
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.
authors.affiliation: Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Preukschas
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulte
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Weber
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.forename: Henning
authors.initials: H
authors.lastname: Sievert
authors.forename: Nora
authors.initials: N
authors.lastname: Pällmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Joachim
authors.initials: J
authors.lastname: Hauber
authors.forename: Melanie
authors.initials: M
authors.lastname: Braig
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002330:Carmustine / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000172:deficiency / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D000077204:Temozolomide; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002330:Carmustine; D003606:Dacarbazine; D006147:Guanine; D008239:Lysine; D006899:Mixed Function Oxygenases; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D000077204:Temozolomide; D000097574:Eukaryotic Translation Initiation Factor 5A; C100667:N(1)-guanyl-1,7-diaminoheptane; C100028:hypusine; C047991:deoxyhypusine hydroxylase; C063507:deoxyhypusine synthase