Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation.
Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation.
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DOI：
10.1016/j.redox.2021.101942
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发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Zhou H
中科院分区：
文献类型：
--
作者：
Sun J;Zhou C;Zhao Y;Zhang X;Chen W;Zhou Q;Hu B;Gao D;Raatz L;Wang Z;Nelson PJ;Jiang Y;Ren N;Bruns CJ;Zhou H
索拉非尼是治疗晚期肝细胞癌的一线分子靶向药物，但其临床疗效有限。在这项研究中，我们确定Quiescin巯基氧化酶1（QSOX 1）作为一种细胞促氧化剂，特别是在索拉非尼治疗HCC的背景下。QSOX 1通过抑制主抗氧化转录因子NRF 2的激活破坏氧化还原稳态并使HCC细胞对氧化应激敏感。在151例HCC患者的肿瘤组织中验证了QSOX 1和NRF 2表达之间的负相关性。在机制上，QSOX 1通过促进EGFR的泛素化介导的降解和加速其细胞内体运输来抑制EGF诱导的EGFR活化，从而抑制NRF 2活性。此外，QSOX 1通过在体外和体内抑制NRF 2增强索拉非尼诱导的铁凋亡。总之，所提供的数据将QSOX 1确定为HCC或其他EGFR依赖性肿瘤类型中基于索拉非尼的联合治疗策略的新候选靶点。QSOX 1通过抑制NRF 2的活化而损害HCC细胞的抗氧化能力。QSOX 1通过加速EGFR信号传导终止抑制NRF2活化。QSOX 1促进HCC中索拉非尼诱导的铁凋亡QSOX 1是HCC患者辅助索拉非尼治疗的潜在生物标志物。
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. QSOX1 impairs the antioxidant capacity of HCC cells by inhibiting NRF2 activation. QSOX1 inhibits NRF2 activation by accelerating EGFR signaling termination. QSOX1 promotes sorafenib-induced ferroptosis in HCC. QSOX1 is a potential biomarker for adjuvant sorafenib treatment in HCC patients.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1126/science.aaw9872
发表时间：
2020-04-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Badgley MA;Kremer DM;Maurer HC;DelGiorno KE;Lee HJ;Purohit V;Sagalovskiy IR;Ma A;Kapilian J;Firl CEM;Decker AR;Sastra SA;Palermo CF;Andrade LR;Sajjakulnukit P;Zhang L;Tolstyka ZP;Hirschhorn T;Lamb C;Liu T;Gu W;Seeley ES;Stone E;Georgiou G;Manor U;Iuga A;Wahl GM;Stockwell BR;Lyssiotis CA;Olive KP
通讯作者：
Olive KP
影响因子：
64.5
作者：
Lignitto, Luca;LeBoeuf, Sarah E.;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
168.9
作者：
Bruix, Jordi;Qin, Shukui;Han, Guohong
通讯作者：
Han, Guohong