Systemic elevation of PTEN induces a tumor-suppressive metabolic state

Isabel Garcia-Cao, Min Sup Song, Robin M. Hobbs, Gaelle Laurent, Carlotta Giorgi, Vincent C.J. De Boer, Dimitrios Anastasiou, Keisuke Ito, Atsuo T. Sasaki, Lucia Rameh, Arkaitz Carracedo, Matthew G. Vander Heiden, Lewis C. Cantley, Paolo Pinton, Marcia C. Haigis, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

231 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)49-62
Number of pages14
JournalCell
Volume149
Issue number1
DOIs
StatePublished - Mar 30 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Garcia-Cao, I., Song, M. S., Hobbs, R. M., Laurent, G., Giorgi, C., De Boer, V. C. J., Anastasiou, D., Ito, K., Sasaki, A. T., Rameh, L., Carracedo, A., Vander Heiden, M. G., Cantley, L. C., Pinton, P., Haigis, M. C., & Pandolfi, P. P. (2012). Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell, 149(1), 49-62. https://doi.org/10.1016/j.cell.2012.02.030