Alpha ketoglutarate levels, regulated by p53 and OGDH, determine autophagy and cell fate/apoptosis in response to Nutlin-3a.
Cancer Biol Ther
; 20(3): 252-260, 2019.
Article
em En
| MEDLINE
| ID: mdl-30289354
ABSTRACT
Activated p53 can promote apoptosis or cell cycle arrest. Differences in energy metabolism can influence cell fate in response to activated p53. Nutlin-3a is a preclinical drug and small molecule activator of p53. Alpha-ketoglutarate (αKG) levels were reduced in cells sensitive to Nutlin-3a-induced apoptosis and increased in cells resistant to this apoptosis. Add-back of a cell-permeable αKG analog (DMKG) rescued cells from apoptosis in response to Nutlin-3a. OGDH is a component of the αKGDH complex that converts αKG to succinate. OGDH knockdown increased endogenous αKG levels and also rescued cells from Nutlin-3a-induced apoptosis. We previously showed reduced autophagy and ATG gene expression contributes to Nutlin-3a-induced apoptosis. DMKG and OGDH knockdown restored autophagy and ATG gene expression in Nutlin-3a-treated cells. These studies indicate αKG levels, regulated by p53 and OGDH, determine autophagy and apoptosis in response to Nutlin-3a.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Proteína Supressora de Tumor p53
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Imidazóis
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Complexo Cetoglutarato Desidrogenase
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Ácidos Cetoglutáricos
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Neoplasias
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos