Mutant p53 blocks SESN1/AMPK/PGC-1α/UCP2 axis increasing mitochondrial O 2-· production in cancer cells

Br J Cancer. 2018 Oct;119(8):994-1008. doi: 10.1038/s41416-018-0288-2. Epub 2018 Oct 15.

Abstract

Background: The TP53 tumor suppressor gene is the most frequently altered gene in tumors and mutant p53 gain-of-function isoforms actively promote cancer malignancy.

Methods: A panel of wild-type and mutant p53 cancer cell lines of different tissues, including pancreas, breast, skin, and lung were used, as well as chronic lymphocytic leukemia (CLL) patients with different TP53 gene status. The effects of mutant p53 were evaluated by confocal microscopy, reactive oxygen species production assay, immunoblotting, and quantitative reverse transcription polymerase chain reaction after cellular transfection.

Results: We demonstrate that oncogenic mutant p53 isoforms are able to inhibit SESN1 expression and consequently the amount of SESN1/AMPK complex, resulting in the downregulation of the AMPK/PGC-1α/UCP2 axis and mitochondrial O2-· production. We also show a correlation between the decrease of reduced thiols with a poorer clinical outcome of CLL patients bearing mutant TP53 gene. The restoration of the mitochondrial uncoupling protein 2 (UCP2) expression, as well as the addition of the radical scavenger N-acetyl-L-cysteine, reversed the oncogenic effects of mutant p53 as cellular hyper-proliferation, antiapoptotic effect, and resistance to drugs.

Conclusions: The inhibition of the SESN1/AMPK/PGC-1α/UCP2 axis contributes to the pro-oxidant and oncogenic effects of mutant p53, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing mutant TP53 gene.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Acetylcysteine / pharmacology*
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Line, Tumor
  • Female
  • Free Radical Scavengers / pharmacology*
  • Heat-Shock Proteins / biosynthesis*
  • Heat-Shock Proteins / metabolism
  • Humans
  • MCF-7 Cells
  • Male
  • Middle Aged
  • Mitochondria / metabolism
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Oxygen / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Protein p53 / genetics*
  • Uncoupling Protein 2 / metabolism*

Substances

  • Free Radical Scavengers
  • Heat-Shock Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Reactive Oxygen Species
  • SESN1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • UCP2 protein, human
  • Uncoupling Protein 2
  • AMP-Activated Protein Kinases
  • Oxygen
  • Acetylcysteine