Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation
Jialei Sun,
Chenhao Zhou,
Yue Zhao,
Xiaofei Zhang,
Wanyong Chen,
Qiang Zhou,
Bo Hu,
Dongmei Gao,
Lisa Raatz,
Zhefang Wang,
Peter J. Nelson,
Yuchao Jiang,
Ning Ren,
Christiane J. Bruns,
Haijun Zhou
Affiliations
Jialei Sun
Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China
Chenhao Zhou
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
Yue Zhao
Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
Xiaofei Zhang
Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
Wanyong Chen
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
Qiang Zhou
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
Bo Hu
Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
Dongmei Gao
Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China
Lisa Raatz
Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
Zhefang Wang
Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany
Peter J. Nelson
Medical Clinic and Policlinic IV, University Clinic, Ludwig-Maximilians-University Munich, Germany
Yuchao Jiang
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Ning Ren
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; Corresponding author. Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
Christiane J. Bruns
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; Corresponding author. Department of General, Visceral, Cancer and Transplant Surgery, University Hospital of Cologne, Cologne, Germany.
Haijun Zhou
Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China; Corresponding author. Liver Cancer Institute & Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis & Cancer Invasion, Fudan University & Ministry of Education, Shanghai, China.
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.
