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| Página principal > Artículos > Artículos publicados > Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells |
(Universitat Autònoma de Barcelona. Institut de Neurociències) (Institut d'Investigació Biomèdica de Bellvitge) (Universitat Autònoma de Barcelona. Servei de Microscòpia) (Institut Català de Nanociència i Nanotecnologia) (Institut Català de Nanociència i Nanotecnologia) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Universitat de Lleida. Departament de Medicina Experimental) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (Universitat Autònoma de Barcelona. Institut de Neurociències) (Universitat Autònoma de Barcelona. Institut de Neurociències) (Institut d'Investigació Biomèdica de Bellvitge) (Universitat Autònoma de Barcelona. Institut de Neurociències)
| Fecha: | 2021 |
| Resumen: | 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. |
| Ayudas: | Agencia Estatal de Investigación SAF2017-83206-R Agencia Estatal de Investigación PGC2018-096003-B-I00 Agencia Estatal de Investigación RTI2018-098027-B-C21 Ministerio de Ciencia e Innovación SEV-2017-0706 |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | Apoptosis ; Caspase-activated DNase (DFF40/CAD) ; Glioblastoma (GBM) ; Gossypol ; Nuclear fragmentation/disassembly |
| Publicado en: | Cancers, Vol. 13, Issue 21 (November 2021) , art. 5579, ISSN 2072-6694 |
