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.
Highlights
Gliomas are the most frequent primary brain tumors in adults
deoxyhypusine synthase (DHS) expression was detected in neurons, ependyma, fibroblasts and pituitary. eukaryotic initiation factor 5A (eIF-5A) was found in neurons, ependyma and pituitary and in meningothelial cells, choroid plexus and some reactive astrocytes
Determination of mRNA and protein levels of eIF-5A, DHS and deoxyhypusine hydroxylase (DOHH) in G55T2 and U87-MG cell lines showed overexpression of eIF-5A and the two hypusine forming enzymes compared to primary human astrocytes
Summary
Gliomas are the most frequent primary brain tumors in adults. As a result of diffuse infiltration, surgical resection of glioblastomas (GBM) is difficult and the tumor usually relapses within months. Tumors become resistant to these therapies e.g. by alterations in growth and survival signalling pathways [3] or expression of DNA repair enzymes [4]. Based on these observations, an extraordinary effort has been made to identify novel therapeutic targets in GBM. An extraordinary effort has been made to identify novel therapeutic targets in GBM In this context a comprehensive list of tumor specific alterations were encountered using new sequencing technologies [5,6]. The disappointing results of current targeted therapies in GBM and the frequent emergence of resistance illustrates the urgent need for potential new molecular targets, which would ideally be independent of the above-mentioned mechanisms
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