title: Systemic elevation of PTEN induces a tumor-suppressive metabolic state.
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.
authors.affiliation: Cancer Genetics Program, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Isabel
authors.initials: I
authors.lastname: Garcia-Cao
authors.forename: Min Sup
authors.initials: MS
authors.lastname: Song
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hobbs
authors.forename: Gaelle
authors.initials: G
authors.lastname: Laurent
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.forename: Vincent C J
authors.initials: VC
authors.lastname: de Boer
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Anastasiou
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ito
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
authors.forename: Lucia
authors.initials: L
authors.lastname: Rameh
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D049628:Body Size; D002452:Cell Count; D049109:Cell Proliferation; D019069:Cell Respiration; D004734:Energy Metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse