Alpha ketoglutarate levels, regulated by p53 and OGDH, determine autophagy and cell fate/apoptosis in response to Nutlin-3a.

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 (?KG) 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 ?KG analog (DMKG) rescued cells from apoptosis in response to Nutlin-3a. OGDH is a component of the ?KGDH complex that converts ?KG to succinate. OGDH knockdown increased endogenous ?KG 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 ?KG levels, regulated by p53 and OGDH, determine autophagy and apoptosis in response to Nutlin-3a.

SUBMITTER: Duan L 

PROVIDER: S-EPMC6370392 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature