Gossypol treatment restores insufficient apoptotic function of dff40/cad in human glioblastoma cells

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*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number5579
JournalCancers
Volume13
Issue number21
DOIs
Publication statusPublished - 1 Nov 2021

Keywords

  • Apoptosis
  • Caspase-activated DNase (DFF40/CAD)
  • Glioblastoma (GBM)
  • Gossypol
  • Nuclear fragmentation/disassembly

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