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Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis

Ophiobolin A (OP-A), a fungal sesterterpene from Bipolaris oryzae, was recently shown to have anti-glioma activity. We show here that OP-A induces paraptosis-like cell death accompanied by dilation of the endoplasmic reticulum (ER) in glioma cells, and that CHOP-mediated ER stress plays a critical r...

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Autores principales: Kim, In Young, Kwon, MiRi, Choi, Min-Koo, Lee, Dongjoo, Lee, Dong Min, Seo, Min Ji, Choi, Kyeong Sook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739770/
https://www.ncbi.nlm.nih.gov/pubmed/29290985
http://dx.doi.org/10.18632/oncotarget.22537
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author Kim, In Young
Kwon, MiRi
Choi, Min-Koo
Lee, Dongjoo
Lee, Dong Min
Seo, Min Ji
Choi, Kyeong Sook
author_facet Kim, In Young
Kwon, MiRi
Choi, Min-Koo
Lee, Dongjoo
Lee, Dong Min
Seo, Min Ji
Choi, Kyeong Sook
author_sort Kim, In Young
collection PubMed
description Ophiobolin A (OP-A), a fungal sesterterpene from Bipolaris oryzae, was recently shown to have anti-glioma activity. We show here that OP-A induces paraptosis-like cell death accompanied by dilation of the endoplasmic reticulum (ER) in glioma cells, and that CHOP-mediated ER stress plays a critical role in this process. OP-A-induced ER-derived dilation and cell death were found to be independent of reactive oxygen species, but were effectively blocked by various thiol antioxidants. We observed that OP-A can react with cysteinyl thiols to form Michael adducts, suggesting that the ability of OP-A to covalently modify free sulfhydryl groups on proteins may cause protein misfolding and the accumulation of misfolded proteins, leading to paraptosis-like cell death. Taken together, these results indicate that the disruption of thiol proteostasis may critically contribute to the anti-glioma activity of OP-A.
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spelling pubmed-57397702017-12-29 Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis Kim, In Young Kwon, MiRi Choi, Min-Koo Lee, Dongjoo Lee, Dong Min Seo, Min Ji Choi, Kyeong Sook Oncotarget Research Paper Ophiobolin A (OP-A), a fungal sesterterpene from Bipolaris oryzae, was recently shown to have anti-glioma activity. We show here that OP-A induces paraptosis-like cell death accompanied by dilation of the endoplasmic reticulum (ER) in glioma cells, and that CHOP-mediated ER stress plays a critical role in this process. OP-A-induced ER-derived dilation and cell death were found to be independent of reactive oxygen species, but were effectively blocked by various thiol antioxidants. We observed that OP-A can react with cysteinyl thiols to form Michael adducts, suggesting that the ability of OP-A to covalently modify free sulfhydryl groups on proteins may cause protein misfolding and the accumulation of misfolded proteins, leading to paraptosis-like cell death. Taken together, these results indicate that the disruption of thiol proteostasis may critically contribute to the anti-glioma activity of OP-A. Impact Journals LLC 2017-11-20 /pmc/articles/PMC5739770/ /pubmed/29290985 http://dx.doi.org/10.18632/oncotarget.22537 Text en Copyright: © 2017 Kim et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Kim, In Young
Kwon, MiRi
Choi, Min-Koo
Lee, Dongjoo
Lee, Dong Min
Seo, Min Ji
Choi, Kyeong Sook
Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
title Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
title_full Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
title_fullStr Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
title_full_unstemmed Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
title_short Ophiobolin A kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
title_sort ophiobolin a kills human glioblastoma cells by inducing endoplasmic reticulum stress via disruption of thiol proteostasis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739770/
https://www.ncbi.nlm.nih.gov/pubmed/29290985
http://dx.doi.org/10.18632/oncotarget.22537
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