Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies.
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Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies. / Preukschas, Michael; Hagel, Christian; Schulte, Alexander; Riecken, Kristoffer; Lamszus, Katrin; Sievert, Henning; Pällmann, Nora; Bokemeyer, Carsten; Hauber, Joachim; Balabanov, Melanie; Balabanov, Stefan.
In: PLOS ONE, Vol. 7, No. 8, 8, 2012, p. 43468.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies.
AU - Preukschas, Michael
AU - Hagel, Christian
AU - Schulte, Alexander
AU - Riecken, Kristoffer
AU - Lamszus, Katrin
AU - Sievert, Henning
AU - Pällmann, Nora
AU - Bokemeyer, Carsten
AU - Hauber, Joachim
AU - Balabanov, Melanie
AU - Balabanov, Stefan
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Aged, 80 and over
KW - Cell Line, Tumor
KW - Gene Knockdown Techniques
KW - Apoptosis/drug effects
KW - Cell Proliferation/drug effects
KW - Cell Cycle/drug effects
KW - Neoplasm Grading
KW - Antineoplastic Agents, Alkylating/pharmacology
KW - Carmustine/pharmacology
KW - Cell Aging/drug effects
KW - Dacarbazine/analogs & derivatives/pharmacology
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Glioblastoma/drug therapy/enzymology/genetics/pathology
KW - Guanine/analogs & derivatives/pharmacology
KW - Lysine/analogs & derivatives/biosynthesis
KW - Mixed Function Oxygenases/genetics/metabolism
KW - Molecular Targeted Therapy
KW - Oxidoreductases Acting on CH-NH Group Donors/antagonists & inhibitors/deficiency/genetics/metabolism
KW - Peptide Initiation Factors/deficiency/genetics
KW - RNA-Binding Proteins/genetics
KW - Adult
KW - Humans
KW - Male
KW - Aged
KW - Female
KW - Aged, 80 and over
KW - Cell Line, Tumor
KW - Gene Knockdown Techniques
KW - Apoptosis/drug effects
KW - Cell Proliferation/drug effects
KW - Cell Cycle/drug effects
KW - Neoplasm Grading
KW - Antineoplastic Agents, Alkylating/pharmacology
KW - Carmustine/pharmacology
KW - Cell Aging/drug effects
KW - Dacarbazine/analogs & derivatives/pharmacology
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Glioblastoma/drug therapy/enzymology/genetics/pathology
KW - Guanine/analogs & derivatives/pharmacology
KW - Lysine/analogs & derivatives/biosynthesis
KW - Mixed Function Oxygenases/genetics/metabolism
KW - Molecular Targeted Therapy
KW - Oxidoreductases Acting on CH-NH Group Donors/antagonists & inhibitors/deficiency/genetics/metabolism
KW - Peptide Initiation Factors/deficiency/genetics
KW - RNA-Binding Proteins/genetics
U2 - 10.1371/journal.pone.0043468
DO - 10.1371/journal.pone.0043468
M3 - SCORING: Journal article
VL - 7
SP - 43468
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 8
M1 - 8
ER -
