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

Cancer Biol Ther. 2019;20(3):252-260. doi: 10.1080/15384047.2018.1523858. Epub 2018 Oct 5.

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.

Keywords: Alpha-ketoglutarate; Nutlin-3a; apoptosis; autophagy; p53.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A549 Cells
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Line, Tumor
  • Gene Knockdown Techniques
  • Glycolysis / drug effects
  • Humans
  • Imidazoles / pharmacokinetics*
  • Ketoglutarate Dehydrogenase Complex / genetics
  • Ketoglutarate Dehydrogenase Complex / metabolism*
  • Ketoglutaric Acids / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Osteosarcoma / drug therapy
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Piperazines / pharmacokinetics*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Imidazoles
  • Ketoglutaric Acids
  • Piperazines
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • nutlin 3
  • Ketoglutarate Dehydrogenase Complex
  • Mechanistic Target of Rapamycin Complex 1