Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation

  • Redox Biol. 2021 May:41:101942. doi: 10.1016/j.redox.2021.101942.
Jialei Sun  1 ,  Chenhao Zhou  2 ,  Yue Zhao  3 ,  Xiaofei Zhang  4 ,  Wanyong Chen  5 ,  Qiang Zhou  6 ,  Bo Hu  7 ,  Dongmei Gao  8 ,  Lisa Raatz  9 ,  Zhefang Wang  10 ,  Peter J Nelson  11 ,  Yuchao Jiang  12 ,  Ning Ren  13 ,  Christiane J Bruns  14 ,  Haijun Zhou  15
Affiliations
  • 1. Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China. Electronic address: [email protected].
  • 2. Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China; Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 3. Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany. Electronic address: [email protected].
  • 4. Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 5. Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Fudan Minhang Academic Health System, And Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 6. Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Fudan Minhang Academic Health System, And Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 7. Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 8. Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China. Electronic address: [email protected].
  • 9. Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany. Electronic address: [email protected].
  • 10. Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany. Electronic address: [email protected].
  • 11. Medical Clinic and Policlinic IV, University Clinic, Ludwig-Maximilians-University Munich, Germany. Electronic address: [email protected].
  • 12. State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 13. Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China; Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Fudan Minhang Academic Health System, And Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 14. Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology (CIO) Achen, Bonn, Cologne and Düsseldorf, Cologne, Germany. Electronic address: [email protected].
  • 15. Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China. Electronic address: [email protected].
PMID: 33770521 DOI: 10.1016/j.redox.2021.101942
Abstract

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), but its clinical effects are still limited. In this study we identify Quiescin sulfhydryl oxidase 1 (QSOX1) acting as a cellular pro-oxidant, specifically in the context of sorafenib treatment of HCC. QSOX1 disrupts redox homoeostasis and sensitizes HCC cells to oxidative stress by inhibiting activation of the master antioxidant transcription factor NRF2. A negative correlation between QSOX1 and NRF2 expression was validated in tumor tissues from 151 HCC patients. Mechanistically, QSOX1 restrains EGF-induced EGFR activation by promoting ubiquitination-mediated degradation of EGFR and accelerating its intracellular endosomal trafficking, leading to suppression of NRF2 activity. Additionally, QSOX1 potentiates sorafenib-induced Ferroptosis by suppressing NRF2 in vitro and in vivo. In conclusion, the data presented identify QSOX1 as a novel candidate target for sorafenib-based combination therapeutic strategies in HCC or Other EGFR-dependent tumor types.

Keywords
Antioxidant; Ferroptosis; HCC; QSOX1; ROS.
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