Lippmann Jana, Petri Kathrin, Fulda Simone, Liese Juliane
Institute for Experimental Cancer Research in Pediatrics, Goethe-University, 60528, Frankfurt, Germany; Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland.
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, University Hospital of Giessen, Giessen Germany; Department of General and Thoracic Surgery, University Hospital of Giessen, Giessen University, Giessen, Germany.
Transl Oncol. 2020 Aug;13(8):100785. doi: 10.1016/j.tranon.2020.100785. Epub 2020 May 13.
Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibrium of ROS in cancer cells has found to be crucial for cell survival, thus increased levels may trigger ferroptosis in HCC. In our study, we investigated the effect of different ROS modulators and ferroptosis inducers on a human HCC cell line and a human hepatoblastoma cell line. We identified a novel synergistic cell death induction by the combination of Auranofin and buthionine sulfoxime (BSO) or by Erastin and BSO at subtoxic concentrations. We found a caspase-independent, redox-regulated cell death, which could be rescued by different inhibitors of ferroptosis. Both cotreatments stimulated lipid peroxidation. All these findings indicated ferroptotic cell death. Both cotreatments affected the canonical ferroptosis pathway through GPX4 downregulation. We also found an accumulation of Nrf2 and HO-1, indicating an additional effect on the non-canonical pathway. Our results implicate that targeting these two main ferroptotic pathways simultaneously can overcome chemotherapy resistance in HCC.
铁死亡是一种新发现的由活性氧（ROS）和脂质过氧化介导的细胞死亡形式，最近已被证明对多种癌症类型有影响；然而，到目前为止，关于其在肝细胞癌（HCC）中的作用的研究还很少。癌细胞中ROS的微妙平衡已被发现对细胞存活至关重要，因此ROS水平升高可能会引发HCC中的铁死亡。在我们的研究中，我们研究了不同的ROS调节剂和铁死亡诱导剂对人HCC细胞系和人肝母细胞瘤细胞系的影响。我们发现金诺芬与丁硫氨酸亚砜胺（BSO）联合使用或依拉司丁与BSO在亚毒性浓度下联合使用可诱导一种新的协同细胞死亡。我们发现了一种不依赖半胱天冬酶的、氧化还原调节的细胞死亡，这种死亡可以被不同的铁死亡抑制剂挽救。两种联合处理均刺激脂质过氧化。所有这些发现均表明存在铁死亡细胞死亡。两种联合处理均通过下调GPX4影响经典的铁死亡途径。我们还发现Nrf2和HO-1的积累，表明对非经典途径有额外影响。我们的结果表明，同时靶向这两条主要的铁死亡途径可以克服HCC中的化疗耐药性。
