Synthetic lethal hubs associated with vincristine resistant neuroblastoma
Synthetic lethal hubs associated with vincristine resistant neuroblastoma
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DOI：
10.1039/c0mb00082e
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发表时间：
2011-01-01
影响因子：
--
通讯作者：
Mayer, Bernd
中科院分区：
文献类型：
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作者：
Fechete, Raul;Barth, Susanne;Mayer, Bernd
癌症的化学疗法经历了许多缺点，包括耐药性的发展。这一事实也适用于使用长春新碱等化疗药物的神经母细胞瘤。我们利用细胞系和人体组织数据对长春新碱耐药相关的分子和细胞机制进行了比较分析。差异基因表达分析揭示了一般耐药机制的分子特征、过程和途径，特别是长春新碱显著涉及肌动蛋白相关特征。然而，特定的耐药模式以及亲本长春新碱敏感细胞的潜在基因型显然表现出显著的异质性。无法得出长春新碱耐药的共识特征，但个体神经母细胞瘤细胞系水平的耐药相关变化以及个体患者特征变得明显。基于这些先决条件，我们利用了合成致死性的概念，旨在鉴定当被抑制时有望诱导细胞死亡的中枢蛋白，这是由于与下调的化学抗性相关特征的合成致死性相互作用。我们的筛选程序鉴定了受肌动蛋白相关过程影响的合成致死中枢蛋白，其将合成致死相互作用保持为在所有测试的化学抗性细胞系中单独发现的下调特征，因此有希望改善治疗窗口。在人神经母细胞瘤组织表达谱中验证此类合成致死中心候选物表明了这种筛选方法用于解决神经母细胞瘤中长春新碱耐药性的可行性。
Chemotherapy of cancer experiences a number of shortcomings including development of drug resistance. This fact also holds true for neuroblastoma utilizing chemotherapeutics as vincristine. We performed a comparative analysis of molecular and cellular mechanisms associated with vincristine resistance utilizing cell line as well as human tissue data. Differential gene expression analysis revealed molecular features, processes and pathways afflicted with drug resistance mechanisms in general, and specifically with vincristine significantly involving actin associated features. However, specific mode of resistance as well as underlying genotype of parental, vincristine sensitive cells apparently exhibited significant heterogeneity. No consensus profile for vincristine resistance could be derived, but resistance-associated changes on the level of individual neuroblastoma cell lines as well as individual patient profiles became clearly evident. Based on these prerequisites we utilized the concept of synthetic lethality aimed at identifying hub proteins which when inhibited promise to induce cell death due to a synthetic lethal interaction with down-regulated, chemoresistance associated features. Our screening procedure identified synthetic lethal hub proteins afflicted with actin associated processes holding synthetic lethal interactions to down-regulated features individually found in all chemoresistant cell lines tested, therefore promising an improved therapeutic window. Verification of such synthetic lethal hub candidates in human neuroblastoma tissue expression profiles indicated the feasibility of this screening approach for addressing vincristine resistance in neuroblastoma.