Subburayan Karthikeyan, Thayyullathil Faisal, Pallichankandy Siraj, Cheratta Anees Rahman, Galadari Sehamuddin
Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates.
Transl Oncol. 2020 Nov;13(11):100843. doi: 10.1016/j.tranon.2020.100843. Epub 2020 Aug 15.
Ferroptosis is a novel form of programmed cell death characterized by an iron-dependent increase in reactive oxygen species (ROS). However, the role of ROS in the regulation of ferroptosis remains elusive. In this study, for the first time, we demonstrate that sodium selenite (SS), a well-established redox-active selenium compound, is a novel inducer of ferroptosis in a variety of human cancer cells. Potent ferroptosis inhibitors, such as ferrostatin-1 (Fer-1) and deferoxamine (DFO), rescue cells from SS-induced ferroptosis. Furthermore, SS down-regulates ferroptosis regulators; solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPx4), while it up-regulates iron accumulation and lipid peroxidation (LPO). These SS-induced ferroptotic responses are achieved via ROS, in particular superoxide (O) generation. Antioxidants such as superoxide dismutase (SOD) and Tiron not only scavenged O production, but also markedly rescued SLC7A11 down-regulation, GSH depletion, GPx4 inactivation, iron accumulation, LPO, and ferroptosis. Moreover, iron chelator DFO significantly reduces the O production, indicating a positive feedback regulation between O production and iron accumulation. Taken together, we have identified SS as a novel ferroptosis inducing agent in various human cancer models.
铁死亡是一种新型的程序性细胞死亡形式，其特征是活性氧（ROS）的铁依赖性增加。然而，ROS在铁死亡调节中的作用仍不清楚。在本研究中，我们首次证明亚硒酸钠（SS），一种成熟的具有氧化还原活性的硒化合物，是多种人类癌细胞中铁死亡的新型诱导剂。强效的铁死亡抑制剂，如铁抑素-1（Fer-1）和去铁胺（DFO），可使细胞免受SS诱导的铁死亡。此外，SS下调铁死亡调节因子；溶质载体家族7成员11（SLC7A11）、谷胱甘肽（GSH）和谷胱甘肽过氧化物酶4（GPx4），同时上调铁积累和脂质过氧化（LPO）。这些SS诱导的铁死亡反应是通过ROS，特别是超氧阴离子（O）的产生来实现的。抗氧化剂如超氧化物歧化酶（SOD）和钛铁试剂不仅清除了O的产生，还显著挽救了SLC7A11的下调、GSH的消耗、GPx4的失活、铁积累、LPO和铁死亡。此外，铁螯合剂DFO显著降低了O的产生，表明O产生与铁积累之间存在正反馈调节。综上所述，我们已确定SS是多种人类癌症模型中的新型铁死亡诱导剂。
