Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation

Cancer Cell. 2019 Feb 11;35(2):191-203.e8. doi: 10.1016/j.ccell.2018.12.012. Epub 2019 Jan 31.


The tumor suppressor p53 is somatically mutated in half of all human cancers. Paradoxically, the wild-type p53 (WTp53) is often retained in certain human cancers, such as hepatocarcinoma (HCC). We discovered a physiological and oncogenic role of WTp53 in suppressing pyruvate-driven oxidative phosphorylation by inducing PUMA. PUMA inhibits mitochondrial pyruvate uptake by disrupting the oligomerization and function of mitochondrial pyruvate carrier (MPC) through PUMA-MPC interaction, which depends on IκB kinase-mediated phosphorylation of PUMA at Ser96/106. High expression levels of PUMA are correlated with decreased mitochondrial pyruvate uptake and increased glycolysis in HCCs and poor prognosis of HCC patients. These findings are instrumental for cancer drug discovery aiming at activating WTp53 or restoring WTp53 activity to p53 mutants.

Keywords: PUMA; glycolysis; mitochondria; mitochondrial pyruvate carrier; oxidative phosphorylation; p53.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation*
  • Glycolysis
  • HCT116 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • I-kappa B Kinase / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Monocarboxylic Acid Transporters / metabolism
  • Oxidative Phosphorylation*
  • Prognosis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Pyruvic Acid / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • MPC1 protein, human
  • MPC2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • Monocarboxylic Acid Transporters
  • PUMA protein, mouse
  • Proto-Oncogene Proteins
  • TP53 protein, human
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Pyruvic Acid
  • I-kappa B Kinase
  • IKBKB protein, human