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

doi:10.1016/j.cell.2012.02.030

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 journal › Article › peer-review

314 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 language	English (US)
Pages (from-to)	49-62
Number of pages	14
Journal	Cell
Volume	149
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2012.02.030
State	Published - Mar 30 2012
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2012.02.030

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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

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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.",

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

note = "Funding Information: We thank M. Bhasin for help with microarray analysis, C. Clower for assistance with PKM splicing assays, W.J. Haveman for mouse genotyping, and Kaitlyn Webster for IHC analysis. I.G.-C. was supported by fellowships from the Human Frontier Science Program (HFSP) and the Spanish Ministry of Education and Science (MEC). This work was supported by NIH grants R01 CA-82328-09 to P.P.P., P01-CA089021 and R01-GM41890 to L.C.C., and Italian Association for Cancer Research (AIRC) grant to P.P.P. ",

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AU - Garcia-Cao, Isabel

AU - Song, Min Sup

AU - Hobbs, Robin M.

AU - Laurent, Gaelle

AU - Giorgi, Carlotta

AU - De Boer, Vincent C.J.

AU - Anastasiou, Dimitrios

AU - Ito, Keisuke

AU - Sasaki, Atsuo T.

AU - Rameh, Lucia

AU - Carracedo, Arkaitz

AU - Vander Heiden, Matthew G.

AU - Cantley, Lewis C.

AU - Pinton, Paolo

AU - Haigis, Marcia C.

AU - Pandolfi, Pier Paolo

N1 - Funding Information: We thank M. Bhasin for help with microarray analysis, C. Clower for assistance with PKM splicing assays, W.J. Haveman for mouse genotyping, and Kaitlyn Webster for IHC analysis. I.G.-C. was supported by fellowships from the Human Frontier Science Program (HFSP) and the Spanish Ministry of Education and Science (MEC). This work was supported by NIH grants R01 CA-82328-09 to P.P.P., P01-CA089021 and R01-GM41890 to L.C.C., and Italian Association for Cancer Research (AIRC) grant to P.P.P.

PY - 2012/3/30

Y1 - 2012/3/30

N2 - 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.

AB - 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.

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Systemic elevation of PTEN induces a tumor-suppressive metabolic state

Abstract

ASJC Scopus subject areas

UN SDGs

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