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Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance

BACKGROUND: Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system x(c)(−),...

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Autores principales: Liu, Nan, Lin, Xiaoli, Huang, Chengying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052275/
https://www.ncbi.nlm.nih.gov/pubmed/31819185
http://dx.doi.org/10.1038/s41416-019-0660-x
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author Liu, Nan
Lin, Xiaoli
Huang, Chengying
author_facet Liu, Nan
Lin, Xiaoli
Huang, Chengying
author_sort Liu, Nan
collection PubMed
description BACKGROUND: Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system x(c)(−), prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells. METHODS: We treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine β-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells. RESULTS: We found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility. CONCLUSIONS: Based on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis.
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spelling pubmed-70522752020-12-10 Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance Liu, Nan Lin, Xiaoli Huang, Chengying Br J Cancer Article BACKGROUND: Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine–glutamate antiporter system x(c)(−), prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells. METHODS: We treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine β-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells. RESULTS: We found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility. CONCLUSIONS: Based on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis. Nature Publishing Group UK 2019-12-10 2020-01-21 /pmc/articles/PMC7052275/ /pubmed/31819185 http://dx.doi.org/10.1038/s41416-019-0660-x Text en © The Author(s), under exclusive licence to Cancer Research UK 2019 https://creativecommons.org/licenses/by/4.0/Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Liu, Nan
Lin, Xiaoli
Huang, Chengying
Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
title Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
title_full Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
title_fullStr Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
title_full_unstemmed Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
title_short Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance
title_sort activation of the reverse transsulfuration pathway through nrf2/cbs confers erastin-induced ferroptosis resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052275/
https://www.ncbi.nlm.nih.gov/pubmed/31819185
http://dx.doi.org/10.1038/s41416-019-0660-x
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AT huangchengying activationofthereversetranssulfurationpathwaythroughnrf2cbsconferserastininducedferroptosisresistance