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

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...

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Autores principales: Sun, Jialei, Zhou, Chenhao, Zhao, Yue, Zhang, Xiaofei, Chen, Wanyong, Zhou, Qiang, Hu, Bo, Gao, Dongmei, Raatz, Lisa, Wang, Zhefang, Nelson, Peter J., Jiang, Yuchao, Ren, Ning, Bruns, Christiane J., Zhou, Haijun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024711/
https://www.ncbi.nlm.nih.gov/pubmed/33770521
http://dx.doi.org/10.1016/j.redox.2021.101942
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author Sun, Jialei
Zhou, Chenhao
Zhao, Yue
Zhang, Xiaofei
Chen, Wanyong
Zhou, Qiang
Hu, Bo
Gao, Dongmei
Raatz, Lisa
Wang, Zhefang
Nelson, Peter J.
Jiang, Yuchao
Ren, Ning
Bruns, Christiane J.
Zhou, Haijun
author_facet Sun, Jialei
Zhou, Chenhao
Zhao, Yue
Zhang, Xiaofei
Chen, Wanyong
Zhou, Qiang
Hu, Bo
Gao, Dongmei
Raatz, Lisa
Wang, Zhefang
Nelson, Peter J.
Jiang, Yuchao
Ren, Ning
Bruns, Christiane J.
Zhou, Haijun
author_sort Sun, Jialei
collection PubMed
description 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.
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spelling pubmed-80247112021-04-13 Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation Sun, Jialei Zhou, Chenhao Zhao, Yue Zhang, Xiaofei Chen, Wanyong Zhou, Qiang Hu, Bo Gao, Dongmei Raatz, Lisa Wang, Zhefang Nelson, Peter J. Jiang, Yuchao Ren, Ning Bruns, Christiane J. Zhou, Haijun Redox Biol Research Paper 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. Elsevier 2021-03-13 /pmc/articles/PMC8024711/ /pubmed/33770521 http://dx.doi.org/10.1016/j.redox.2021.101942 Text en © 2021 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Paper
Sun, Jialei
Zhou, Chenhao
Zhao, Yue
Zhang, Xiaofei
Chen, Wanyong
Zhou, Qiang
Hu, Bo
Gao, Dongmei
Raatz, Lisa
Wang, Zhefang
Nelson, Peter J.
Jiang, Yuchao
Ren, Ning
Bruns, Christiane J.
Zhou, Haijun
Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation
title Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation
title_full Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation
title_fullStr Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation
title_full_unstemmed Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation
title_short Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation
title_sort quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving egfr endosomal trafficking and inhibiting nrf2 activation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024711/
https://www.ncbi.nlm.nih.gov/pubmed/33770521
http://dx.doi.org/10.1016/j.redox.2021.101942
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