Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State

被引：387

作者：

Garcia-Cao, Isabel ^{[1
,2
]}

Song, Min Sup ^{[1
,2
]}

Hobbs, Robin M. ^{[1
,2
]}

Laurent, Gaelle ^{[3
]}

Giorgi, Carlotta ^{[4
,5
]}

de Boer, Vincent C. J. ^{[3
]}

Anastasiou, Dimitrios ^{[6
]}

Ito, Keisuke ^{[1
,2
]}

Sasaki, Atsuo T. ^{[6
]}

Rameh, Lucia ^{[7
]}

Carracedo, Arkaitz ^{[1
,2
]}

Vander Heiden, Matthew G. ^{[8
]}

Cantley, Lewis C. ^{[6
]}

Pinton, Paolo ^{[4
,5
]}

Haigis, Marcia C. ^{[3
]}

Pandolfi, Pier Paolo ^{[1
,2
]}

机构：

[1] Harvard Univ, Sch Med, Canc Genet Program, Beth Israel Deaconess Canc Ctr,Dept Med, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Med Ctr, Boston, MA 02215 USA

[3] Harvard Univ, Sch Med, Dept Cell Biol, Paul F Glenn Labs Biol Mech Aging, Boston, MA 02115 USA

[4] Univ Ferrara, ICSI, Dept Expt & Diagnost Med, Sect Gen Pathol, I-44100 Ferrara, Italy

[5] Univ Ferrara, LTTA Ctr, I-44100 Ferrara, Italy

[6] Harvard Univ, Sch Med, Dept Syst Biol,Beth Israel Deaconess Med Ctr, Dept Med,Div Signal Transduct, Boston, MA 02115 USA

[7] Boston Biomed Res Inst, Watertown, MA 02472 USA

[8] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

来源：

CELL | 2012年 / 149卷 / 01期

关键词：

DNA-DAMAGE RESPONSE; C-MYC; CELL-SIZE; SIGNALING PATHWAY; PYRUVATE-KINASE; PHOSPHOINOSITIDE; 3-KINASE; CANCER SUSCEPTIBILITY; GROWTH; DROSOPHILA; EXPRESSION;

D O I：

10.1016/j.cell.2012.02.030

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：49 / 62

页数：14

共 75 条

[1]

Subtle variations in Pten dose determine cancer susceptibility [J].