Estudi de la desestructuració del nucli induïda per gossypol en cèl·lules humanes de glioblastoma deficients en la fragmentació nuclear apoptòtica
- Autores: Laura Martínez Escardó
- Directores de la Tesis: Víctor J. Yuste Mateos (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2020
- Idioma: español
- ISBN: 9788449096204
- Tribunal Calificador de la Tesis: Abelardo López Rivas (presid.), José Ramon Bayascas Ramírez (secret.), Roger Palou Marin (voc.)
- Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Apoptosis, a tightly regulated form of cell death, involves a caspase-triggered cascade of biochemical and morphological events. The activation of the DNA Fragmentation Factor, 40-kDa Subunit, or Caspase-activated Deoxyribonuclease (DFF40/CAD) is considered a key event allowing dying cells to show classical apoptotic nuclear changes. The apoptotic nuclear morphology is depicted by chromatin condensation into highly-packaged round masses and fragmentation of the nucleus.
Glioblastoma, a particularly aggressive solid brain tumor, is characterized by extreme resistance to apoptosis. Among the possibilities that could explain glioblastoma resistance to most of the drugs used in the clinic, our group pointed out the impossibility of glioblastoma cells to undergo complete apoptotic cell death (Sanchez-Osuna et al., 2014) and reported an intrinsic DFF40/CAD endonuclease deficiency as a common trait in human glioblastoma cells (Sanchez-Osuna et al., 2016). When faced to different cytotoxic compounds, the predominant behavior of glioblastoma cells is to show a DFF40/CAD-independent nuclear morphology characterized by a unique mass of compacted chromatin in the absence of nuclear fragmentation.
This Doctoral Thesis evidence that, despite the deficient expression of DFF40/CAD, human glioblastoma cells can switch its predominant nuclear aspect to a DFF40/CAD-dependent apoptotic nuclear morphology when challenged with an adequate stimulus. Gossypol is here reported as an adequate insult able to trigger a proper activation of caspases and DFF40/CAD in human glioblastoma cells. However, a limited number of cells show this nuclear morphology after gossypol treatment. In this sense, our results evidence an unfavorable intracellular context in human glioblastoma cells impeding the proper function of DFF40/CAD as an endonuclease regardless of its levels. Here, we point to intracellular metal ions, such as iron or copper, as intracellular candidates that may contribute to glioblastoma cells’ refractoriness to display apoptotic nuclear morphology after different cytotoxic insults. Moreover, besides metal ions, an accurate modulation of autophagy is here suggested to be critical to allow apoptotic nuclear morphology in glioblastoma cells.
The comprehension of this nuclear outcome is of particular interest since an accurate fragmentation and packaging of the genomic content constitute a fundamental process to prevent the spreading of harmful genes and to facilitate the elimination of apoptotic cells. Reduced efficiency in the removal of apoptotic cells with DNA damage may contribute to tumorigenesis. Since different effects may derive from different modes of cell death, the knowledge of the specific intracellular mechanisms that become activated when facing tumor cells to chemotherapeutic treatments is essential to understand better the biological consequences that may derive from this therapeutic approach.
