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Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling

Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (T...

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Autores principales: Zhang, Weifan, Gong, Mengyuan, Zhang, Wunai, Mo, Jiantao, Zhang, Simei, Zhu, Zeen, Wang, Xueni, Zhang, Bo, Qian, Weikun, Wu, Zheng, Ma, Qingyong, Wang, Zheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300693/
https://www.ncbi.nlm.nih.gov/pubmed/35859150
http://dx.doi.org/10.1038/s41419-022-05082-3
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author Zhang, Weifan
Gong, Mengyuan
Zhang, Wunai
Mo, Jiantao
Zhang, Simei
Zhu, Zeen
Wang, Xueni
Zhang, Bo
Qian, Weikun
Wu, Zheng
Ma, Qingyong
Wang, Zheng
author_facet Zhang, Weifan
Gong, Mengyuan
Zhang, Wunai
Mo, Jiantao
Zhang, Simei
Zhu, Zeen
Wang, Xueni
Zhang, Bo
Qian, Weikun
Wu, Zheng
Ma, Qingyong
Wang, Zheng
author_sort Zhang, Weifan
collection PubMed
description Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (TST) has been reported to exert antitumor effects, its role in pancreatic cancer and the underlying mechanisms remain unclear. In this study, we found that TST reduced the viability and clonogenesis of pancreatic cancer cell lines, along with intracellular iron overload, increasing reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) overexpression, and glutathione peroxidase (GSH-PX) depletion. Mechanistically, chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays were used to confirm that signal transducer and activator of transcription 3 (STAT3) binds to the GPX4 promoter region and promotes its transcription, whereas TST blocked GPX4 expression by regulating STAT3. Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling.
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spelling pubmed-93006932022-07-22 Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling Zhang, Weifan Gong, Mengyuan Zhang, Wunai Mo, Jiantao Zhang, Simei Zhu, Zeen Wang, Xueni Zhang, Bo Qian, Weikun Wu, Zheng Ma, Qingyong Wang, Zheng Cell Death Dis Article Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (TST) has been reported to exert antitumor effects, its role in pancreatic cancer and the underlying mechanisms remain unclear. In this study, we found that TST reduced the viability and clonogenesis of pancreatic cancer cell lines, along with intracellular iron overload, increasing reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) overexpression, and glutathione peroxidase (GSH-PX) depletion. Mechanistically, chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays were used to confirm that signal transducer and activator of transcription 3 (STAT3) binds to the GPX4 promoter region and promotes its transcription, whereas TST blocked GPX4 expression by regulating STAT3. Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling. Nature Publishing Group UK 2022-07-20 /pmc/articles/PMC9300693/ /pubmed/35859150 http://dx.doi.org/10.1038/s41419-022-05082-3 Text en © The Author(s) 2022, corrected publication 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Weifan
Gong, Mengyuan
Zhang, Wunai
Mo, Jiantao
Zhang, Simei
Zhu, Zeen
Wang, Xueni
Zhang, Bo
Qian, Weikun
Wu, Zheng
Ma, Qingyong
Wang, Zheng
Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling
title Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling
title_full Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling
title_fullStr Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling
title_full_unstemmed Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling
title_short Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling
title_sort thiostrepton induces ferroptosis in pancreatic cancer cells through stat3/gpx4 signalling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300693/
https://www.ncbi.nlm.nih.gov/pubmed/35859150
http://dx.doi.org/10.1038/s41419-022-05082-3
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