Mutant p53 prevents GAPDH nuclear translocation in pancreatic cancer cells favoring glycolysis and 2-deoxyglucose sensitivity.
Biochim Biophys Acta Mol Cell Res
; 1865(12): 1914-1923, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-30296496
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating human malignancies. In about 70% of PDACs the tumor suppressor gene TP53 is mutated generally resulting in conformational changes of mutant p53 (mutp53) proteins, which acquire oncogenic functions triggering aggressiveness of cancers and alteration of energetic metabolism. Here, we demonstrate that mutant p53 prevents the nuclear translocation of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) stabilizing its cytoplasmic localization, thus supporting glycolysis of cancer cells and inhibiting cell death mechanisms mediated by nuclear GAPDH. We further show that the prevention of nuclear localization of GAPDH is mediated by both stimulation of AKT and repression of AMPK signaling, and is associated with the formation of the SIRT1GAPDH complex. By using siRNA-GAPDH or an inhibitor of the enzyme, we functionally demonstrate that the maintenance of GAPDH in the cytosol has a critical impact on the anti-apoptotic and anti-autophagic effects driven by mutp53. Furthermore, the blockage of its mutp53-dependent cytoplasmic stabilization is able to restore the sensitivity of PDAC cells to the treatment with gemcitabine. Finally, our data suggest that mutp53-dependent enhanced glycolysis permits cancer cells to acquire sensitivity to anti-glycolytic drugs, such as 2-deoxyglucose, suggesting a potential personalized therapeutic approach in human cancers carrying mutant TP53 gene.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Núcleo Celular
/
Proteína Supressora de Tumor p53
/
Carcinoma Ductal Pancreático
/
Desoxiglucose
/
Gliceraldeído-3-Fosfato Desidrogenases
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article