Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells

Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DF...

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Autores principales:	Laura Martínez-Escardó, Montse Alemany, María Sánchez-Osuna, Alejandro Sánchez-Chardi, Meritxell Roig-Martínez, Salvio Suárez-García, Daniel Ruiz-Molina, Noemi Vidal, Gerard Plans, Carles Majós, Judit Ribas, María Antonia Baltrons, Jose R. Bayascas, Carlos Barcia, Jordi Bruna, Victor J. Yuste
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	apoptosis caspase-activated DNase (DFF40/CAD) glioblastoma (GBM) gossypol nuclear fragmentation/disassembly Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/6413408650f8453789322c010a859186
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spelling	oai:doaj.org-article:6413408650f8453789322c010a8591862021-11-11T15:35:55ZGossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells10.3390/cancers132155792072-6694https://doaj.org/article/6413408650f8453789322c010a8591862021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5579https://doaj.org/toc/2072-6694Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DFF40/CAD is the main endonuclease implicated in apoptotic nuclear disassembly. To be properly activated, DFF40/CAD should reside in the cytosol. However, the endonuclease is poorly expressed in the cytosol and remains cumulated in the nucleus of GBM cells. Here, by employing commercial and non-commercial patient-derived GBM cells, we demonstrate that the natural terpenoid aldehyde gossypol prompts DFF40/CAD-dependent nuclear fragmentation. A comparative analysis between gossypol- and staurosporine-treated cells evidenced that levels of neither caspase activation nor DNA damage were correlated with the ability of each compound to induce nuclear fragmentation. Deconvoluted confocal images revealed that DFF40/CAD was almost completely excluded from the nucleus early after the staurosporine challenge. However, gossypol-treated cells maintained DFF40/CAD in the nucleus for longer times, shaping a ribbon-like structure piercing the nuclear fragments and building a network of bridged masses of compacted chromatin. Therefore, GBM cells can fragment their nuclei if treated with the adequate insult, making the cell death process irreversible.Laura Martínez-EscardóMontse AlemanyMaría Sánchez-OsunaAlejandro Sánchez-ChardiMeritxell Roig-MartínezSalvio Suárez-GarcíaDaniel Ruiz-MolinaNoemi VidalGerard PlansCarles MajósJudit RibasMaría Antonia BaltronsJose R. BayascasCarlos BarciaJordi BrunaVictor J. YusteMDPI AGarticleapoptosiscaspase-activated DNase (DFF40/CAD)glioblastoma (GBM)gossypolnuclear fragmentation/disassemblyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5579, p 5579 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	apoptosis caspase-activated DNase (DFF40/CAD) glioblastoma (GBM) gossypol nuclear fragmentation/disassembly Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	apoptosis caspase-activated DNase (DFF40/CAD) glioblastoma (GBM) gossypol nuclear fragmentation/disassembly Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Laura Martínez-Escardó Montse Alemany María Sánchez-Osuna Alejandro Sánchez-Chardi Meritxell Roig-Martínez Salvio Suárez-García Daniel Ruiz-Molina Noemi Vidal Gerard Plans Carles Majós Judit Ribas María Antonia Baltrons Jose R. Bayascas Carlos Barcia Jordi Bruna Victor J. Yuste Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells
description	Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process. DFF40/CAD is the main endonuclease implicated in apoptotic nuclear disassembly. To be properly activated, DFF40/CAD should reside in the cytosol. However, the endonuclease is poorly expressed in the cytosol and remains cumulated in the nucleus of GBM cells. Here, by employing commercial and non-commercial patient-derived GBM cells, we demonstrate that the natural terpenoid aldehyde gossypol prompts DFF40/CAD-dependent nuclear fragmentation. A comparative analysis between gossypol- and staurosporine-treated cells evidenced that levels of neither caspase activation nor DNA damage were correlated with the ability of each compound to induce nuclear fragmentation. Deconvoluted confocal images revealed that DFF40/CAD was almost completely excluded from the nucleus early after the staurosporine challenge. However, gossypol-treated cells maintained DFF40/CAD in the nucleus for longer times, shaping a ribbon-like structure piercing the nuclear fragments and building a network of bridged masses of compacted chromatin. Therefore, GBM cells can fragment their nuclei if treated with the adequate insult, making the cell death process irreversible.
format	article
author	Laura Martínez-Escardó Montse Alemany María Sánchez-Osuna Alejandro Sánchez-Chardi Meritxell Roig-Martínez Salvio Suárez-García Daniel Ruiz-Molina Noemi Vidal Gerard Plans Carles Majós Judit Ribas María Antonia Baltrons Jose R. Bayascas Carlos Barcia Jordi Bruna Victor J. Yuste
author_facet	Laura Martínez-Escardó Montse Alemany María Sánchez-Osuna Alejandro Sánchez-Chardi Meritxell Roig-Martínez Salvio Suárez-García Daniel Ruiz-Molina Noemi Vidal Gerard Plans Carles Majós Judit Ribas María Antonia Baltrons Jose R. Bayascas Carlos Barcia Jordi Bruna Victor J. Yuste
author_sort	Laura Martínez-Escardó
title	Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells
title_short	Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells
title_full	Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells
title_fullStr	Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells
title_full_unstemmed	Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells
title_sort	gossypol treatment restores insufficient apoptotic function of dff40/cad in human glioblastoma cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/6413408650f8453789322c010a859186
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Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells

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