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Treatment of Neuroblastoma Cells with Inhibitors of Protein Disulfide Isomerase Upregulates NQO1 Activity.
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2020-07-14 , DOI: 10.1021/acs.chemrestox.0c00101
Dennis Özcelik 1
Affiliation  

Hallmarks of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease include oxidative stress, accumulation of unfolded proteins, and neuronal cell death. One key player in maintaining redox homeostasis and oxidative protein folding is the protein disulfide isomerase (PDI). PDI has been the focus of drug discovery studies in neurodegenerative diseases, which have reported, paradoxically, that PDI inhibition is neuroprotective in cellular disease models. This study investigated the molecular implications of PDI inhibition by examining the effect of the PDI inhibitors securinine and 16F16 on the gene expression profile of SH-SY5Y neuroblastoma cells. Microarray analysis identified 36 genes that were differentially expressed in both inhibitor treatments. Computational approaches revealed that these differentially expressed genes are involved in apoptosis and cell death and that they are part of a protein–protein interaction network. Among the 36 identified genes, NAD(P)H quinone dehydrogenase 1 (NQO1) displayed the highest average expression change. As a central player in the cellular oxidative stress response, NQO1 was the focus of further investigation. Immunoblotting confirmed the increased expression level of NQO1, and activity assays demonstrated substantial increases in NQO1 activity in SH-SY5Y cells after treatment with PDI inhibitors. In summary, this study suggests a novel link between PDI inhibition and NQO1 activity, providing insights into the dynamic interplay between protein folding, oxidative stress, and cell death in neurodegenerative diseases, which can be exploited for drug development in the future.

中文翻译:

用蛋白质二硫化物异构酶抑制剂处理神经母细胞瘤细胞上调 NQO1 活性。

阿尔茨海默病和帕金森病等神经退行性疾病的标志包括氧化应激、未折叠蛋白的积累和神经元细胞死亡。维持氧化还原稳态和氧化蛋白质折叠的一个关键参与者是蛋白质二硫键异构酶 (PDI)。PDI 一直是神经退行性疾病药物发现研究的重点,自相矛盾的是,PDI 抑制在细胞疾病模型中具有神经保护作用。本研究通过检查 PDI 抑制剂叶秋碱和 16F16 对 SH-SY5Y 神经母细胞瘤细胞基因表达谱的影响,研究了 PDI 抑制的分子意义。微阵列分析确定了在两种抑制剂治疗中差异表达的 36 个基因。计算方法表明,这些差异表达的基因参与细胞凋亡和细胞死亡,并且它们是蛋白质-蛋白质相互作用网络的一部分。在 36 个鉴定的基因中,NAD(P)H 醌脱氢酶 1 (NQO1) 显示出最高的平均表达变化。作为细胞氧化应激反应的核心参与者,NQO1 是进一步研究的重点。免疫印迹证实 NQO1 的表达水平增加,活性测定表明,在用 PDI 抑制剂处理后,SH-SY5Y 细胞中 NQO1 的活性显着增加。总之,这项研究表明 PDI 抑制和 NQO1 活性之间存在新的联系,提供了对蛋白质折叠、氧化应激和神经退行性疾病中细胞死亡之间动态相互作用的见解,
更新日期:2020-08-17
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