Sepantronium bromide (YM-155) is believed to elicit apoptosis and mitotic arrest in tumor cells by reducing (BIRC5, survivin) mRNA. In this study, we monitored changes in survivin mRNA and protein after treating MDA-MB-231 cells with YM-155 concurrent with evaluation of whole transcriptomic (WT) mRNA and long intergenic non-coding RNA at 2 time points: 8 h sub-lethal (83 ng/mL) and 20 h at the LC₅₀ (14.6 ng/mL). The data show a tight association between cell death and the precipitating loss of survivin protein and mRNA (-2.67 fold-change (FC), p<0.001) at 20 h, questioning if the decline in survivin is attributed to cell death or drug impact. The meager loss of survivin mRNA was overshadowed by enormous differential change to the WT in both magnitude and significance for over 2000 differentially up/down-regulated transcripts: (+22 FC to -12 FC, p<0.001). The data show YM-155 to up-regulate transcripts in control of circadian rhythm (NOCT, PER, BHLHe40, NFIL3), tumor suppression (SIK1, FOSB), histone methylation (KDM6B) and negative feedback of NF-kappa B signaling (TNFAIP3). Down-regulated transcripts by YM-155 include glucuronidase (GUSBP3), numerous micro-RNAs, DNA damage repair elements (CENPI, POLQ, RAD54B) and the most affected system was the ataxia-telangiectasia mutated (ATM)/Fanconi anemia E3 monoubiquitin ligase core complexes (FANC transcripts - A/B/E/F/G/M), FANC2, FANCI, BRCA1, BRCA2, RAD51, PALB2 gene and ATR (ATM- and Rad3-Related) pathway. In conclusion, these findings suggest that a primary target of YM-155 is the loss of replicative DNA repair systems.

中文翻译：

---

Sepantronium Bromide (YM-155) 对 MDA-MB-231 细胞全转录组的影响：强调 ATR/ATM Fanconi 贫血 DNA 损伤反应受损。

Sepantronium bromide (YM-155) 被认为通过减少 (BIRC5, survivin) mRNA 在肿瘤细胞中引起细胞凋亡和有丝分裂停滞。在这项研究中，我们在 2 个时间点监测了用 YM-155 处理 MDA-MB-231 细胞后生存素 mRNA 和蛋白质的变化，同时评估了全转录组 (WT) mRNA 和长基因间非编码 RNA：8 小时亚致死 (83 ng/mL) 和 20 小时 LC ₅₀(14.6 纳克/毫升)。数据显示细胞死亡与 20 小时时 survivin 蛋白和 mRNA 的沉淀损失（-2.67 倍变化 (FC)，p<0.001）之间存在密切关联，质疑 survivin 的下降是否归因于细胞死亡或药物影响. 对于 2000 多个差异上调/下调的转录本，WT 在幅度和意义上的巨大差异变化掩盖了生存素 mRNA 的微薄损失：（+22 FC 至 -12 FC，p<0.001）。数据显示 YM-155 上调转录本以控制昼夜节律（NOCT、PER、BHLHe40、NFIL3）、肿瘤抑制（SIK1、FOSB）、组蛋白甲基化（KDM6B）和 NF-kappa B 信号传导的负反馈（TNFAIP3） ）。YM-155 下调的转录物包括葡萄糖醛酸酶 (GUSBP3)、大量微 RNA、DNA 损伤修复元件 (CENPI、POLQ、RAD54B)，受影响最大的系统是共济失调毛细血管扩张症突变 (ATM)/范可尼贫血 E3 单泛素连接酶核心复合物 (FANC 转录本 - A/B/E/F/G/M)、FANC2、FANCI、BRCA1、BRCA2、RAD51 , PALB2 基因和 ATR (ATM- and Rad3-Related) 通路。总之，这些发现表明 YM-155 的主要目标是复制 DNA 修复系统的丧失。