Article

BNIP3 induction, controlled by p53/PTEN, favours mitophagy and apoptosis on behalf of necrosis, being a marker of better prognosis in glioma

Berta Segura-Collar2, Vega Garcia-Escudero1,3,4, Andrés Romero-Bravo2, Marta Izquierdo1, Pilar Sánchez-Gómez2* and Ricardo Gargini1, 2*

1 Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), C/ Nicolás Cabrera 1, Universidad Autónoma Madrid, 28049 Madrid, Spain;

2 Unidad de Neuro-Oncología, Instituto de Salud Carlos III (ISCIII), Madrid, Spain;

3 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain;

4Departamento de Anatomía, Histología y Neurociencia. Facultad de Medicina, Universidad Autónoma Madrid, C/ del Arzobispo Morcillo 4, 28029 Madrid, Spain;

*Correspondence to: psanchezg@isciii.es  and ragargini@cbm.csic.es Tel: + 34911964592

 

Abstract

The WHO definition of high-grade gliomas relies on the presence of microvascular proliferation and/or tumor necrosis. New genetic data provide deeper understanding of different cell death processes and thus strengthen the link between the mechanism governing the establishment and progression to highly aggressive tumors such as glioblastoma. Apoptosis, necrosis and autophagy are important in the development of cancer but how they take place and how are regulated is poorly understood. Here we show that there is a profound alteration of the genes of mitophagy in glioma. Specifically, the lack of BNIP3 copies correlates with increasing glioma degree. In addition, these alterations in BNIP3 show a distribution associated to cell death processes and p53 mutations. By using a mitochondrial stress inducing system, we have observed that BNIP3 regulates mitochondrial potential loss therefore triggering cell death with apoptotic or necrotic properties depending on p53 status. P53 mutant cells show necrosis characteristics lacking mitophagy activation. On the contrary, p53 wild type cells demonstrate mitophagy activation, mitochondrial potential loss and apoptosis hallmarks. Chemical inhibition of PTEN-PI3K-AKT pathway also leads to apoptosis activation similar to p53 wild type condition. In conclusion, the type of death generated by the mitochondrial and oxidative stress based system depends on p53 and PTEN-PI3K-AKT status, which can lead to cell death with apoptotic or necrotic traits, being the first associated with less aggressive gliomas.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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