RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer
RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer
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DOI：
10.3389/fphar.2018.01371
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发表时间：
2018-11-22
影响因子：
5.6
通讯作者：
Xie, Tian
中科院分区：
文献类型：
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作者：
Sui, Xinbing;Zhang, Ruonan;Xie, Tian
铁下垂是一种铁依赖的氧化性细胞死亡，其特征是铁依赖的活性氧物种(ROS)在细胞内积累。它与包括癌症在内的各种人类疾病有关。最近，铁下垂作为一种非凋亡性的细胞死亡形式，出现在特定的癌症类型中；然而，它与结直肠癌(CRC)的相关性尚未被探索，并且仍不清楚。在这里，我们发现铁下垂诱导剂RSL3在24小时内启动了HCT116、LoVo和HT29 CRC细胞的细胞死亡和ROS积累。此外，我们还发现在RSL3处理的CRC细胞中，ROS水平和转铁蛋白表达增加，同时谷胱甘肽过氧化物酶4(Gpx4)的表达降低，这表明铁依赖的细胞死亡，铁下垂。过表达Gpx4导致RSL3处理后细胞死亡减少。因此，RSL3能够以剂量和时间依赖的方式在体外诱导三种不同的大肠癌细胞株发生铁下垂，这是由于ROS增加和细胞内活性铁库的增加所致。此外，Gpx4的过表达能够逆转这一效应。综上所述，我们的结果表明，铁下垂的诱导导致了RSL3诱导的结直肠癌细胞死亡，铁下垂可能是一种普遍存在的、动态的癌症治疗细胞死亡形式。
Ferroptosis is an iron-dependent, oxidative cell death, and is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. It has been implicated in various human diseases, including cancer. Recently, ferroptosis, as a non-apoptotic form of cell death, is emerging in specific cancer types; however, its relevance in colorectal cancer (CRC) is unexplored and remains unclear. Here, we showed that ferroptosis inducer RSL3 initiated cell death and ROS accumulation in HCT116, LoVo, and HT29 CRC cells over a 24 h time course. Furthermore, we found that ROS levels and transferrin expression were elevated in CRC cells treated with RSL3 accompanied by a decrease in the expression of glutathione peroxidase 4 (GPX4), indicating an iron-dependent cell death, ferroptosis. Overexpression GPX4 resulted in decreased cell death after RSL3 treatment. Therefore, RSL3 was able to induce ferroptosis on three different CRC cell lines in vitro in a dose-and time-dependent manner, which was due to increased ROS and an increase in the cellular labile iron pool. Moreover, this effect was able to be reversed by overexpression of GPX4. Taken together, our results suggest that the induction of ferroptosis contributed to RSL3-induced cell death in CRC cells and ferroptosis may be a pervasive and dynamic form of cell death for cancer treatment.