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首页> 外文期刊>Acta Biochimica Polonica >Analysis of genes involved in response to doxorubicin and a GD2 ganglioside-specific 14G2a monoclonal antibody in IMR-32 human neuroblastoma cells
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Analysis of genes involved in response to doxorubicin and a GD2 ganglioside-specific 14G2a monoclonal antibody in IMR-32 human neuroblastoma cells

机译：IMR-32人成神经细胞瘤细胞中与阿霉素和GD2神经节苷脂特异性14G2a单克隆抗体应答有关的基因分析

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摘要

Neuroblastoma is the most common extra-cranial solid tumor of childhood and it is characterized by the presence of a glycosphingolipid, GD2 ganglioside. Monoclonal antibodies targeting the antigen are currently tested in clinical trials. Additionally, several research groups reported results revealing that ganglioside-specific antibodies can affect cellular signaling and cause direct cytotoxicity against tumor cells. To shed more light on gene expression signatures of tumor cells, we used microarrays to analyze changes of transcriptome in IMR-32 human neuroblastoma cell cultures treated with doxorubicin (DOX) or a mouse monoclonal antibody binding to GD2 ganglioside 14G2a (mAb) for 24 h. The obtained results highlight that disparate cellular pathways are regulated by doxorubicin and 14G2a. Next, we used RT-PCR to verify mRNA levels of selected DOX-responsive genes such as RPS27L, PPM1D, SESN1, CDKN1A, TNFSF10B, and 14G2a-responsive genes such as SVIL, JUN, RASSF6, TLX2, ID1. Then, we applied western blot and analyzed levels of RPS27L, PPM1D, sestrin 1 proteins after DOX-treatment. Additionally, we aimed to measure effects of doxorubicin and topotecan (TPT) and 14G2a on expression of a novel human NDUFAF2 gene encoding for mimitin protein (MYC-induced mitochondrial protein) and correlate it with expression of the MYCN gene. We showed that expression of both genes was concomitantly decreased in the 14G2a-treated IMR-32 cells after 24 h and 48 h. Our results extend knowledge on gene expression profiles after application of DOX and 14G2a in our model and reveal promising candidates for further research aimed at finding novel anti-neuroblastoma targets.
机译：神经母细胞瘤是儿童时期最常见的颅外实体瘤，其特征是存在糖鞘脂GD2神经节苷脂。目前正在临床试验中测试靶向抗原的单克隆抗体。此外，几个研究小组报告的结果表明，神经节苷脂特异性抗体可影响细胞信号传导并引起针对肿瘤细胞的直接细胞毒性。为了更加了解肿瘤细胞的基因表达特征，我们使用微阵列分析了用阿霉素（DOX）或结合GD2神经节苷脂14G2a（mAb）的小鼠单克隆抗体处理了24 h的IMR-32人成神经细胞瘤细胞培养物中转录组的变化。获得的结果表明，不同的细胞途径受阿霉素和14G2a的调节。接下来，我们使用RT-PCR验证选定的DOX响应基因（例如RPS27L，PPM1D，SESN1，CDKN1A，TNFSF10B）和14G2a响应基因（例如SVIL，JUN，RASSF6，TLX2，ID1）的mRNA水平。然后，我们进行了蛋白质印迹，并分析了DOX处理后RPS27L，PPM1D，sestrin 1蛋白的水平。此外，我们旨在测量阿霉素和托泊替康（TPT）和14G2a对新型人NDUFAF2基因表达的影响，该基因编码mimitin蛋白（MYC诱导的线粒体蛋白），并将其与MYCN基因的表达相关联。我们显示，在24小时和48小时后，在14G2a处理的IMR-32细胞中，这两个基因的表达均随之降低。我们的研究结果扩展了在模型中应用DOX和14G2a后对基因表达谱的认识，并揭示了有希望的候选物，可用于寻找新的抗神经母细胞瘤靶标。

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