Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies.
Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies.
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胶质母细胞瘤患者样本中真核起始因子 5A 和高尿苷形成酶的表达：对新靶向治疗的影响。
DOI：
10.1371/journal.pone.0043468
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Balabanov S
中科院分区：
文献类型：
--
作者：
Preukschas M;Hagel C;Schulte A;Weber K;Lamszus K;Sievert H;Pällmann N;Bokemeyer C;Hauber J;Braig M;Balabanov S
胶质母细胞瘤是高度侵袭性的成人脑肿瘤，临床结果较差。尽管有广泛的新的和更具体的治疗策略，胶质母细胞瘤的治疗仍然具有挑战性，在所有情况下肿瘤复发。最近的研究表明，真核生物起始因子5A（eIF-5A）的翻译后羟腐胺赖氨酸修饰是细胞增殖、分化的重要调节因子，也是肿瘤形成、发展和维持的重要因素。在这里，我们报告eIF-5A以及羟腐胺赖氨酸形成酶脱氧羟腐胺赖氨酸合成酶（DHS）和脱氧羟腐胺赖氨酸羟化酶（DOHH）在胶质母细胞瘤患者样本中高度过表达。重要的是，靶向eIF-5A和其羟腐胺赖氨酸修饰与GC 7，一种特异性DHS抑制剂，显示出很强的抗增殖作用，在胶质母细胞瘤细胞系在体外，而正常的人星形胶质细胞不受影响。此外，我们确定了p53依赖性早衰，一种永久性的细胞周期停滞，作为用GC 7处理后U87-MG细胞的主要结果。引人注目的是，与临床相关的烷化剂和GC 7的组合治疗在胶质母细胞瘤细胞系中具有相加的抗增殖作用。此外，通过短发夹RNA（shRNA）稳定敲低eIF-5A和DHS可以模拟GC 7的抗增殖作用。这些研究结果表明，药理学抑制eIF-5A可能代表了一种新的概念，以治疗胶质母细胞瘤，并可能有助于大大改善这种肿瘤实体的临床过程。
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.
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影响因子：
4.4
作者：
Jenkins, ZA;Hååg, PG;Johansson, HE
通讯作者：
Johansson, HE
影响因子：
8.8
作者：
Günther, W;Pawlak, E;Damasceno, R;Arnold, H;Terzis, AJ
通讯作者：
Terzis, AJ
影响因子：
50.3
作者：
Bachoo, RM;Maher, EA;DePinho, RA
通讯作者：
DePinho, RA
影响因子：
158.5
作者：
Hegi, ME;Diserens, A;Stupp, R
通讯作者：
Stupp, R
DOI：
10.1073/pnas.95.1.224
发表时间：
1998-01-06
影响因子：
11.1
作者：
Kyrpides, NC;Woese, CR
通讯作者：
Woese, CR