Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State
Menée sur des souris génétiquement modifiées pour que leurs cellules expriment un niveau élevé de la protéine PTEN, cette étude met en évidence un mécanisme de régulation négative du métabolisme des cellules tumorales par PTEN
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. º Super-PTEN mice are viable and show reduced body size due to decreased cell number º PTEN elevation shifts cellular metabolism to a tumor-suppressive anti-Warburg state º PTEN controls key metabolic pathways through PI3K-dependent and -independent functions º PTEN negatively impacts tumor metabolic pathways: glycolysis and glutaminolysis Increasing the expression of PTEN protects mice from cancer by suppressing metabolic programs, such as aerobic glycolysis, that fuel tumor growth. The findings indicate that cellular metabolic programs can play an important role in cancer prevention.
Cell , résumé, 2011