Kaipa Jagan Mohan, Starkuviene Vytaute, Erfle Holger, Eils Roland, Gladilin Evgeny
Helmholtz Center for Infection Research, Braunschweig, Germany.
BioQuant, University Heidelberg, Heidelberg, Germany.
PeerJ. 2020 Dec 16;8:e10373. doi: 10.7717/peerj.10373. eCollection 2020.
Silibinin (SIL), a natural flavonolignan from the milk thistle (Silybum marianum), is known to exhibit remarkable hepatoprotective, antineoplastic and EMT inhibiting effects in different cancer cells by targeting multiple molecular targets and pathways. However, the predominant majority of previous studies investigated effects of this phytocompound in a one particular cell line. Here, we carry out a systematic analysis of dose-dependent viability response to SIL in five non-small cell lung cancer (NSCLC) lines that gradually differ with respect to their intrinsic EMT stage. By correlating gene expression profiles of NSCLC cell lines with the pattern of their SIL IC50 response, a group of cell cycle, survival and stress responsive genes, including some prominent targets of STAT3 (BIRC5, FOXM1, BRCA1), was identified. The relevancy of these computationally selected genes to SIL viability response of NSCLC cells was confirmed by the transient knockdown test. In contrast to other EMT-inhibiting compounds, no correlation between the SIL IC50 and the intrinsic EMT stage of NSCLC cells was observed. Our experimental results show that SIL viability response of differently constituted NSCLC cells is linked to a subnetwork of tightly interconnected genes whose transcriptomic pattern can be used as a benchmark for assessment of individual SIL sensitivity instead of the conventional EMT signature. Insights gained in this study pave the way for optimization of customized adjuvant therapy of malignancies using Silibinin.
水飞蓟宾（SIL）是一种从水飞蓟（Silybum marianum）中提取的天然黄酮木脂素，已知它通过靶向多种分子靶点和信号通路，在不同癌细胞中表现出显著的肝保护、抗肿瘤和抑制上皮-间质转化（EMT）的作用。然而，以前的大多数研究都只在一种特定的细胞系中研究这种植物化合物的作用。在这里，我们对五种非小细胞肺癌（NSCLC）细胞系进行了系统分析，这些细胞系在其内在的EMT阶段逐渐有所不同，分析了它们对水飞蓟宾剂量依赖性的生存反应。通过将NSCLC细胞系的基因表达谱与其水飞蓟宾IC50反应模式相关联，确定了一组细胞周期、生存和应激反应基因，包括一些STAT3的重要靶点（BIRC5、FOXM1、BRCA1）。通过瞬时敲低试验证实了这些通过计算选择的基因与NSCLC细胞对水飞蓟宾生存反应的相关性。与其他抑制EMT的化合物不同，未观察到水飞蓟宾IC50与NSCLC细胞的内在EMT阶段之间存在相关性。我们的实验结果表明，不同组成的NSCLC细胞对水飞蓟宾的生存反应与一个紧密相连的基因子网有关，其转录组模式可作为评估个体对水飞蓟宾敏感性的基准，而不是传统的EMT特征。本研究中获得的见解为使用水飞蓟宾优化恶性肿瘤的定制辅助治疗铺平了道路。
