New paper in Cancers – Gossypol treatment restores insufficient apoptotic function in human Glioblastoma cells

New paper in Cancers – Gossypol treatment restores insufficient apoptotic function in human Glioblastoma cells

11 Nov 2021

New publication in Cancers journal entitled “Gossypol treatment restores insufficient apoptotic function of DFF40/CAD in human Glioblastoma cells” by Laura Martínez-Escardó as the main author and led by Prof. Victor Yuste (Institut de Neurociències – INc UAB). The work has had the contribution from the Nanosfun group.

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. The aim of the authors was to assess whether this endonuclease could be activated to facilitate nuclear fragmentation in GBM cells. The results 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.

ABSTRACT: 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.

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Funding: This work was supported by grants SAF2017-83206-R funded by MCIN/Government of Spain (to V.J.Y.), SLT008/18/00028 from the CERCA Program/Generalitat de Catalunya (to J.B.), PGC2018-096003-B-I00 funded by MCI/AEI/10.130339/501100011033 and by ERDF A way of making Europe (to C.B.), and RTI2018-098027-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by ERDF A way of making Europe (to D.R.-M.). The ICN2 is supported by the Severo Ochoa Centres of Excellence Program, grant SEV-2017-0706 funded by MCIN/AEI/10.13039/501100011033. The ICN2 is under the CERCA Program/Generalitat de Catalunya. L.M.-E. was recipient of a “Personal Investigador en Formació” fellow (BQ-2016-2) from Universitat Autònoma de Barcelona, and later supported by Oncobell program (IDIBELL).