Chinese Medicinal Research and Development Center, China Medical University Hospital, Taichung 40447, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan.
Department of Animal Science, National Chung Hsing University, Taichung 40227, Taiwan.
Cancer Lett. 2018 Mar 1;416:124-137. doi: 10.1016/j.canlet.2017.12.025. Epub 2017 Dec 20.
Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. BAY 11-7085 (BAY), which is a well-known IκBα inhibitor, suppressed viability in cancer cells via induction of ferroptotic death in an NF-κB-independent manner. Reactive oxygen species scavenging, relief of lipid peroxidation, replenishment of glutathione and thiol-containing agents, as well as iron chelation, rescued BAY-induced cell death. BAY upregulated a variety of Nrf2 target genes related to redox regulation, particularly heme oxygenase-1 (HO-1). Studies with specific inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2-SLC7A11-HO-1. SLC7A11 inhibition by erastin, sulfasalazine, or shRNA interference sensitizes BAY-induced cell death. Overexperession of SLC7A11 attenuated BAY-inhibited cell viability. The ferroptotic process induced by hHO-1 overexpression further indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates through cellular redox regulation and iron accumulation. BAY causes compartmentalization of HO-1 into the nucleus and mitochondrion, and followed mitochondrial dysfunctions, leading to lysosome targeting for mitophagy. In this study, we first discovered that BAY induced ferroptosis via Nrf2-SLC7A11-HO-1 pathway and HO-1 is a key mediator by responding to the cellular redox status.
铁死亡是一种氧化细胞死亡形式，已成为癌症治疗的化疗靶点。BAY 11-7085（BAY）是一种著名的 IκBα抑制剂，通过非 NF-κB 依赖性方式诱导铁死亡来抑制癌细胞活力。活性氧清除、脂质过氧化缓解、谷胱甘肽和含巯基的试剂补充以及铁螯合，挽救了 BAY 诱导的细胞死亡。BAY 上调了与氧化还原调节相关的多种 Nrf2 靶基因，特别是血红素加氧酶-1（HO-1）。用特异性抑制剂和 shRNA 干预的研究表明，诱导的层次是 Nrf2-SLC7A11-HO-1。用 erastin、柳氮磺胺吡啶或 shRNA 干扰抑制 SLC7A11 可使 BAY 诱导的细胞死亡敏感。SLC7A11 的过度表达减弱了 BAY 抑制的细胞活力。hHO-1 过表达诱导的铁死亡过程进一步表明，HO-1 是 BAY 诱导的铁死亡的关键介质，通过细胞氧化还原调节和铁积累起作用。BAY 导致 HO-1 区室化到核和线粒体中，并随后导致线粒体功能障碍，导致溶酶体靶向自噬。在这项研究中，我们首次发现 BAY 通过 Nrf2-SLC7A11-HO-1 途径诱导铁死亡，HO-1 是通过响应细胞氧化还原状态的关键介质。
