Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor
Decomposition profile data analysis of multiple drug effects identifies endoplasmic reticulum stress-inducing ability as an unrecognized factor
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DOI：
10.1038/s41598-020-70140-9
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发表时间：
2020-08-04
影响因子：
4.6
通讯作者：
Kusuhara, Hiroyuki
中科院分区：
文献类型：
--
作者：
Morita, Katsuhisa;Mizuno, Tadahaya;Kusuhara, Hiroyuki
化学品在生物系统中具有多种作用。由于它们的靶效应在输出中占主导地位，它们的脱靶效应往往被忽视，有时可能导致危险的不良事件。最近，我们开发了一种新的分解剖面数据分析方法，正交线性分离分析（OLSA），分析多重效应。在这项研究中，我们测试了OLSA是否确定了药物诱导内质网（ER）应激的能力，作为一个以前未被认识到的因素。在分析了用不同化学物质处理的MCF 7细胞的转录组谱之后，我们将重点放在以众所周知的ER应激诱导剂（如环孢素A）为特征的载体上。我们选择了五种药物预测为未识别的ER应激诱导剂，基于他们的诱导能力得分来自OLSA。这些药物实际上以浓度依赖性方式诱导MCF 7细胞中的X-box结合蛋白1剪接，这是ER应激的指标。五种测试化合物的两种结构不同的代表在HepG 2和HuH 7细胞中表现出相似的结果，但在来源于人肝嵌合小鼠的PXB原代肝细胞中没有表现出相似的结果。这些结果表明，我们使用OLSA的分解策略揭示了药物的ER应激诱导能力是一种未识别的效应，其表现取决于细胞的背景。
Chemicals have multiple effects in biological systems. Because their on-target effects dominate the output, their off-target effects are often overlooked and can sometimes cause dangerous adverse events. Recently, we developed a novel decomposition profile data analysis method, orthogonal linear separation analysis (OLSA), to analyse multiple effects. In this study, we tested whether OLSA identified the ability of drugs to induce endoplasmic reticulum (ER) stress as a previously unrecognized factor. After analysing the transcriptome profiles of MCF7 cells treated with different chemicals, we focused on a vector characterized by well-known ER stress inducers, such as ciclosporin A. We selected five drugs predicted to be unrecognized ER stress inducers, based on their inducing ability scores derived from OLSA. These drugs actually induced X-box binding protein 1 splicing, an indicator of ER stress, in MCF7 cells in a concentration-dependent manner. Two structurally different representatives of the five test compounds exhibited similar results in HepG2 and HuH7 cells, but not in PXB primary hepatocytes derived from human-liver chimeric mice. These results indicate that our decomposition strategy using OLSA uncovered the ER stress-inducing ability of drugs as an unrecognized effect, the manifestation of which depended on the background of the cells.