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Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully un...

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Autores principales: Liu, Chen-Chi, Li, Hsin-Hsien, Lin, Jiun-Han, Chiang, Ming-Chen, Hsu, Tien-Wei, Li, Anna Fen-Yau, Yen, David Hung-Tsang, Hsu, Han-Shui, Hung, Shih-Chieh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773805/
https://www.ncbi.nlm.nih.gov/pubmed/35053196
http://dx.doi.org/10.3390/biom12010048
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author Liu, Chen-Chi
Li, Hsin-Hsien
Lin, Jiun-Han
Chiang, Ming-Chen
Hsu, Tien-Wei
Li, Anna Fen-Yau
Yen, David Hung-Tsang
Hsu, Han-Shui
Hung, Shih-Chieh
author_facet Liu, Chen-Chi
Li, Hsin-Hsien
Lin, Jiun-Han
Chiang, Ming-Chen
Hsu, Tien-Wei
Li, Anna Fen-Yau
Yen, David Hung-Tsang
Hsu, Han-Shui
Hung, Shih-Chieh
author_sort Liu, Chen-Chi
collection PubMed
description Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma.
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spelling pubmed-87738052022-01-21 Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway Liu, Chen-Chi Li, Hsin-Hsien Lin, Jiun-Han Chiang, Ming-Chen Hsu, Tien-Wei Li, Anna Fen-Yau Yen, David Hung-Tsang Hsu, Han-Shui Hung, Shih-Chieh Biomolecules Article Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma. MDPI 2021-12-29 /pmc/articles/PMC8773805/ /pubmed/35053196 http://dx.doi.org/10.3390/biom12010048 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Chen-Chi
Li, Hsin-Hsien
Lin, Jiun-Han
Chiang, Ming-Chen
Hsu, Tien-Wei
Li, Anna Fen-Yau
Yen, David Hung-Tsang
Hsu, Han-Shui
Hung, Shih-Chieh
Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway
title Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway
title_full Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway
title_fullStr Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway
title_full_unstemmed Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway
title_short Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway
title_sort esophageal cancer stem-like cells resist ferroptosis-induced cell death by active hsp27-gpx4 pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773805/
https://www.ncbi.nlm.nih.gov/pubmed/35053196
http://dx.doi.org/10.3390/biom12010048
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