p53-regulated autophagy is controlled by glycolysis and determines cell fate

Oncotarget. 2015 Sep 15;6(27):23135-56. doi: 10.18632/oncotarget.5218.


The tumor suppressor p53 regulates downstream targets that determine cell fate. Canonical p53 functions include inducing apoptosis, growth arrest, and senescence. Non-canonical p53 functions include its ability to promote or inhibit autophagy and its ability to regulate metabolism. The extent to which autophagy and/or metabolic regulation determines cell fate by p53 is unclear. To address this, we compared cells resistant or sensitive to apoptosis by the p53 activator Nutlin-3a. In resistant cells, glycolysis was maintained upon Nutlin-3a treatment, and activated p53 promoted prosurvival autophagy. In contrast, in apoptosis sensitive cells activated p53 increased superoxide levels and inhibited glycolysis through repression of glycolytic pathway genes. Glycolysis inhibition and increased superoxide inhibited autophagy by repressing ATG genes essential for autophagic vesicle maturation. Inhibiting glycolysis increased superoxide and blocked autophagy in apoptosis-resistant cells, causing p62-dependent caspase-8 activation. Finally, treatment with 2-DG or the autophagy inhibitors chloroquine or bafilomycin A1 sensitized resistant cells to Nutlin-3a-induced apoptosis. Together, these findings reveal novel links between glycolysis and autophagy that determine apoptosis-sensitivity in response to p53. Specifically, the findings indicate 1) that glycolysis plays an essential role in autophagy by limiting superoxide levels and maintaining expression of ATG genes required for autophagic vesicle maturation, 2) that p53 can promote or inhibit autophagy depending on the status of glycolysis, and 3) that inhibiting protective autophagy can expand the breadth of cells susceptible to Nutlin-3a induced apoptosis.

Keywords: Nutlin-3a; autophagy; glycolysis; p53.

Publication types

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

MeSH terms

  • Apoptosis
  • Autophagy
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Cell Lineage*
  • Cell Survival
  • Cellular Senescence
  • Chloroquine / chemistry
  • Flow Cytometry
  • Glycolysis*
  • Humans
  • Imidazoles / metabolism*
  • MCF-7 Cells
  • Macrolides / chemistry
  • Microscopy, Confocal
  • Microscopy, Electron
  • Microscopy, Electron, Transmission
  • Oxygen / chemistry
  • Piperazines / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA, Small Interfering / metabolism
  • Superoxides / metabolism
  • Tumor Suppressor Protein p53 / metabolism*


  • Imidazoles
  • Macrolides
  • Piperazines
  • RNA, Small Interfering
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Superoxides
  • nutlin 3
  • Chloroquine
  • bafilomycin A1
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • CASP8 protein, human
  • Caspase 8
  • Oxygen