Arsenic is reportedly a biphasic inorganic compound for its toxicity and anticancer effects in humans [1, 2]. Recent studies have shown that certain arsenic compounds including arsenic hexoxide (AS4O6; hereafter, AS6) induce programmed cell death and cell cycle arrest in human cancer cells and murine cancer models [3, 4]. However, the mechanisms by which AS6 suppresses cancer cells are incompletely understood. In this study, we report the mechanisms of AS6 through transcriptome analyses. In particular, the cytotoxicity and global gene expression regulation by AS6 were compared in human normal and cancer breast epithelial cells. Using RNA-sequencing and bioinformatics analyses, differentially expressed genes in significantly affected biological pathways in these cell types were validated by real-time quantitative polymerase chain reaction and immunoblotting assays. Our data show markedly differential effects of AS6 on cytotoxicity and gene expression in human mammary epithelial normal cells (HUMEC) and Michigan Cancer Foundation 7 (MCF7), a human mammary epithelial cancer cell line. AS6 selectively arrests cell growth and induces cell death in MCF7 cells without affecting the growth of HUMEC in a dose-dependent manner. AS6 alters the transcription of a large number of genes in MCF7 cells, but much fewer genes in HUMEC. Importantly, we found that the cell proliferation, cell cycle, and DNA repair pathways are significantly suppressed whereas cellular stress response and apoptotic pathways increase in AS6-treated MCF7 cells. Together, we provide the first evidence of differential effects of AS6 on normal and cancerous breast epithelial cells, suggesting that AS6 at moderate concentrations induces cell cycle arrest and apoptosis through modulating genome-wide gene expression, leading to compromised DNA repair and increased genome instability selectively in human breast cancer cells.

中文翻译：

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六氧化二砷对人原代乳腺上皮细胞和MCF7细胞的细胞增殖和全基因组基因表达有不同的影响

据报道，砷是一种双相无机化合物，对人体具有毒性和抗癌作用[1，2]。最近的研究表明，某些砷化合物，包括六氧化二砷（AS4O6；以下称AS6），可在人癌细胞和鼠类癌症模型中诱导程序性细胞死亡和细胞周期停滞[3，4]。但是，AS6抑制癌细胞的机制尚不完全清楚。在这项研究中，我们通过转录组分析报告了AS6的机制。特别是，在人正常和乳腺癌乳腺上皮细胞中比较了AS6的细胞毒性和整体基因表达调控。使用RNA测序和生物信息学分析，通过实时定量聚合酶链反应和免疫印迹测定法验证了在这些细胞类型中受显着影响的生物学途径中的差异表达基因。我们的数据显示，AS6对人乳腺上皮正常细胞（HUMEC）和人乳腺上皮癌细胞系密歇根癌症基金会7（MCF7）的细胞毒性和基因表达具有明显的差异作用。AS6选择性抑制细胞生长并诱导MCF7细胞死亡，而不会以剂量依赖的方式影响HUMEC的生长。AS6可以改变MCF7细胞中大量基因的转录，而改变HUMEC中的基因要少得多。重要的是，我们发现细胞增殖，细胞周期，DNA和DNA修复途径被显着抑制，而经AS6处理的MCF7细胞的细胞应激反应和凋亡途径增加。在一起，我们提供了AS6对正常和癌性乳腺癌上皮细胞的不同作用的第一个证据，表明中等浓度的AS6通过调节全基因组基因表达诱导细胞周期停滞和凋亡，从而导致受损的DNA修复和选择性增加的基因组不稳定性在人类乳腺癌细胞中。