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

被引：134

作者：

Sun, Jialei ^{[1
,2
,3
,4
]}

Zhou, Chenhao ^{[1
,2
,3
,4
,5
]}

Zhao, Yue ^{[8
]}

Zhang, Xiaofei ^{[9
,10
]}

Chen, Wanyong ^{[5
,6
,7
]}

Zhou, Qiang ^{[5
,6
,7
]}

Hu, Bo ^{[5
]}

Gao, Dongmei ^{[1
,2
,3
,4
]}

Raatz, Lisa ^{[8
]}

Wang, Zhefang ^{[8
]}

Nelson, Peter J. ^{[11
]}

Jiang, Yuchao ^{[12
]}

Ren, Ning ^{[1
,2
,3
,4
,5
,6
,7
]}

Bruns, Christiane J. ^{[8
,13
]}

Zhou, Haijun ^{[1
,2
,3
,4
]}

机构：

[1] Fudan Univ, Liver Canc Inst, Shanghai, Peoples R China

[2] Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China

[3] Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Shanghai, Peoples R China

[4] Minist Educ, Shanghai, Peoples R China

[5] Fudan Univ, Zhongshan Hosp, Dept Liver Surg, Shanghai, Peoples R China

[6] Fudan Univ, Minhang Hosp, Inst Fudan Minhang Acad Hlth Syst, Key Lab Whole Period Monitoring & Precise Interve, Shanghai 200032, Peoples R China

[7] Fudan Univ, AHS, Shanghai 200032, Peoples R China

[8] Univ Hosp Cologne, Dept Gen Visceral Canc & Transplant Surg, Cologne, Germany

[9] Fudan Univ, Huashan Hosp, Dept Gen Surg, Shanghai, Peoples R China

[10] Fudan Univ, Canc Metastasis Inst, Shanghai, Peoples R China

[11] Ludwig Maximilians Univ Munchen, Univ Clin, Med Clin & Policlin 4, Munich, Germany

[12] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai, Peoples R China

[13] Ctr Integrated Oncol CIO Achen Bonn Cologne & Dus, Cologne, Germany

来源：

REDOX BIOLOGY | 2021年 / 41卷

关键词：

QSOX1; HCC; ROS; Antioxidant; Ferroptosis; OXIDATIVE STRESS; CELL-SURVIVAL; CANCER-CELLS; METABOLISM; MECHANISMS; INVASION; RECEPTOR; DEATH;

D O I：

10.1016/j.redox.2021.101942

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 prooxidant, 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.

引用

页数：19

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