Systemic elevation of PTEN induces a tumor-suppressive metabolic state

Cell. 2012 Mar 30;149(1):49-62. doi: 10.1016/j.cell.2012.02.030. Epub 2012 Mar 6.

Abstract

Decremental loss of PTEN results in cancer susceptibility and tumor progression. PTEN elevation might therefore be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with PTEN expression elevated to varying levels by taking advantage of bacterial artificial chromosome (BAC)-mediated transgenesis. The "Super-PTEN" mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake and increased mitochondrial oxidative phosphorylation and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and -independent pathways and negatively impacting two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Size
  • Cell Count
  • Cell Proliferation
  • Cell Respiration
  • Energy Metabolism
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • Signal Transduction*

Substances

  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Phosphatidylinositol 3-Kinases
  • PTEN Phosphohydrolase
  • Pten protein, mouse

Associated data

  • GEO/GSE35670