Chuchu Feng1, Yu Wu1, Yantao Chen2, Xilin Xiong1, Peng Li3, Xiaomin Peng1, Chunmou Li1, Wenjun Weng1, Yafeng Zhu4, Dunhua Zhou5, Yang Li6. 1. Department of Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Yan Jiang Xi Road, No. 107, Guangzhou, 510120, China. 2. Department of Orthopaedics, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Yan Jiang Xi Road, No. 107, Guangzhou, 510120, China. 3. Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Kaiyuan Avenue, No. 190, Guangzhou, 510530, China. 4. Medical Researcher Center, Sun Yat-Sen University Memorial Hospital, Sun Yet-Sen University, Yan Jiang Xi Road, No. 107, Guangzhou, 510120, China. 5. Department of Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Yan Jiang Xi Road, No. 107, Guangzhou, 510120, China. zhoudunh@mail.sysu.edn.cn. 6. Department of Pediatric Hematology/Oncology, Sun Yet-Sen Memorial Hospital, Sun Yet-Sen University, Yan Jiang Xi Road, No. 107, Guangzhou, 510120, China. liyang5@mail.sysu.edu.cn.
Abstract
BACKGROUND: Neuroblastoma (NB) is the most common extracranial tumor in central nervous system threatening children's health with limited therapeutic options. Arsenic trioxide (ATO) has been identified the cytotoxicity in NB cells but the potential mechanism remains unclear. In this study, we attempted to obtain some insight into the mechanisms of cell death induced by ATO in NB cells. METHODS AND RESULTS: Proteomic analyses found that ATO can affect the signaling pathway associated with ferroptosis, including the upregulation of iron absorption (FTL, FTH1, HO-1), ferritinophagy (LC3, P62, ATG7, NCOA4) and modifier of glutathione synthesis (GCLM); downregulation of glutamine synthetase (GS) and GPX4, which was the critical inhibitor of ferroptosis. Western blot analysis revealing GPX4 expression in SK-N-BE (2) cells decreased after treatment with ATO (7.3 µM), resulting in a loss of GPX4 activity. Furthermore, Ferroptosis inhibitor ferrostatin-1 partially blocked ATO-induced cell death. CONCLUSIONS: Our study revealed that ATO may induce ferroptosis in neuroblastoma cell SK-N-BE (2) by facilitating the downregulation of GPX4, ultimately resulting in iron-dependent oxidative death.
BACKGROUND: Neuroblastoma (NB) is the most common extracranial tumor in central nervous system threatening children's health with limited therapeutic options. Arsenic trioxide (ATO) has been identified the cytotoxicity in NB cells but the potential mechanism remains unclear. In this study, we attempted to obtain some insight into the mechanisms of cell death induced by ATO in NB cells. METHODS AND RESULTS: Proteomic analyses found that ATO can affect the signaling pathway associated with ferroptosis, including the upregulation of iron absorption (FTL, FTH1, HO-1), ferritinophagy (LC3, P62, ATG7, NCOA4) and modifier of glutathione synthesis (GCLM); downregulation of glutamine synthetase (GS) and GPX4, which was the critical inhibitor of ferroptosis. Western blot analysis revealing GPX4 expression in SK-N-BE (2) cells decreased after treatment with ATO (7.3 µM), resulting in a loss of GPX4 activity. Furthermore, Ferroptosis inhibitor ferrostatin-1 partially blocked ATO-induced cell death. CONCLUSIONS: Our study revealed that ATO may induce ferroptosis in neuroblastoma cell SK-N-BE (2) by facilitating the downregulation of GPX4, ultimately resulting in iron-dependent oxidative death.
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