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Article

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

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Cell Death, Senescence and Survival Group, Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Facultat de Medicina, Campus de Bellaterra, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
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Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (C.I.B.E.R.N.E.D.), Campus de Bellaterra, 08193 Bellaterra, Spain
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Neuro-Oncology Unit, Hospital Universitari de Bellvitge-ICO L’Hospitalet (IDIBELL), 089098 Barcelona, Spain
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Servei de Microscopia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
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Neuroimmunity Research Group, Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
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Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, 08193 Bellaterra, Spain
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Pharmacology of Cellular Stress Group, Pharmacology Unit, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida/IRBLleida, 25198 Lleida, Spain
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Signalling in the Central Nervous System Group, Departament de Bioquímica i Biologia Molecular, Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
*
Author to whom correspondence should be addressed.
Second co-authors.
Academic Editors: Axel H. Schönthal and Chiara Laezza
Cancers 2021, 13(21), 5579; https://doi.org/10.3390/cancers13215579
Received: 3 September 2021 / Revised: 30 October 2021 / Accepted: 5 November 2021 / Published: 8 November 2021
(This article belongs to the Section Molecular Cancer Biology)
Human glioblastoma (GBM) cells are particularly resistant to nuclear fragmentation upon cytotoxic insult. To date, nuclear disassembly is the biological point-of-no-return of the apoptotic process. The injured cell that does not go beyond this point goes into a failed apoptosis and has potential for recovery. Nuclear disassembly is governed by caspases and, ultimately, by DFF40/CAD endonuclease. GBM cells express low levels of DFF40/CAD protein. Our aim was to assess whether this endonuclease could be activated to facilitate nuclear fragmentation in GBM cells. We revealed that GBM cells can activate their nuclear pool of DFF40/CAD in a caspase-dependent manner when treated with gossypol. Gossypol enabled DFF40/CAD assembly into high-order structures, facilitating nuclear dismantling. The identification of such compounds, pushing cells toward the point-of-no-return of apoptosis, will provide new tools to hamper the recovery of injured cells, slowing down tumor progression.
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. View Full-Text
Keywords: apoptosis; caspase-activated DNase (DFF40/CAD); glioblastoma (GBM); gossypol; nuclear fragmentation/disassembly apoptosis; caspase-activated DNase (DFF40/CAD); glioblastoma (GBM); gossypol; nuclear fragmentation/disassembly
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MDPI and ACS Style

Martínez-Escardó, L.; Alemany, M.; Sánchez-Osuna, M.; Sánchez-Chardi, A.; Roig-Martínez, M.; Suárez-García, S.; Ruiz-Molina, D.; Vidal, N.; Plans, G.; Majós, C.; Ribas, J.; Baltrons, M.A.; Bayascas, J.R.; Barcia, C.; Bruna, J.; Yuste, V.J. Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells. Cancers 2021, 13, 5579. https://doi.org/10.3390/cancers13215579

AMA Style

Martínez-Escardó L, Alemany M, Sánchez-Osuna M, Sánchez-Chardi A, Roig-Martínez M, Suárez-García S, Ruiz-Molina D, Vidal N, Plans G, Majós C, Ribas J, Baltrons MA, Bayascas JR, Barcia C, Bruna J, Yuste VJ. Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells. Cancers. 2021; 13(21):5579. https://doi.org/10.3390/cancers13215579

Chicago/Turabian Style

Martínez-Escardó, Laura, 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, and Victor J. Yuste. 2021. "Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells" Cancers 13, no. 21: 5579. https://doi.org/10.3390/cancers13215579

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