Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimize its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and reactive oxygen species production were analysed in A549 cells. FOXO3a subcellular localization was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin.

中文翻译：

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甲基硒酸通过抑制Akt通过FOXO3a核易位而促进抗肿瘤作用。

硒补充剂已在临床试验中显示出降低各种癌症（包括肺癌）风险的能力。先前的研究报道，甲基硒酸（MSA）在癌细胞中的抗增殖和促凋亡活性可以通过抑制PI3K途径来介导。对MSA下游细胞靶标的更好理解将提供有关其作用机理的信息，并将有助于优化其与PI3K抑制剂联合治疗的使用。对于本研究，分析了MSA对A549细胞的存活力，细胞周期，代谢，凋亡，蛋白质和mRNA表达以及活性氧产生的影响。在A549细胞和稳定转染的人骨肉瘤U2foxRELOC细胞中检查了FOXO3a亚细胞定位。我们的结果表明，MSA在稳定表达GFP-FOXO3a的A549细胞和U2OS细胞中诱导FOXO3a核易位。有趣的是，另一种硒化合物亚硒酸钠尽管诱导了细胞凋亡，但并未对FOXO3a易位产生任何显着影响。DNA的单链断裂，肿瘤细胞代谢适应的破坏，ROS产生的减少以及G1中的细胞周期停滞以及诱导细胞凋亡是在A549细胞中MSA处理24小时后发生的晚期事件。我们的发现表明FOXO3a是MSA抗增殖作用的相关介质。MSA机理作用的这一新证据可为开发其抗肿瘤特性和新颖组合疗法的最佳设计开辟新途径。