Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent Manner

被引：721

作者：

Kalender, Adem ^{[1
,2
]}

Selvaraj, Anand ^{[1
,2
]}

Kim, So Young ^{[2
,3
]}

Gulati, Pawan ^{[1
]}

Brule, Sophie ^{[4
,5
]}

Viollet, Benoit ^{[6
,7
]}

Kemp, Bruce E. ^{[8
]}

Bardeesy, Nabeel ^{[9
]}

Dennis, Patrick ^{[1
]}

Schlager, John J. ^{[10
]}

Marette, Andre ^{[4
,5
]}

Kozma, Sara C. ^{[1
,2
]}

Thomas, George ^{[1
,2
]}

机构：

[1] Univ Cincinnati, Dept Canc & Cell Biol, Metab Dis Inst, Cincinnati, OH 45237 USA

[2] Friedrich Miescher Inst Biomed Res, CH-4058 Basel, Switzerland

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Laval Univ Hosp Res Ctr, Dept Anat & Physiol, Ste Foy, PQ G1V 4G5, Canada

[5] Laval Univ Hosp Res Ctr, Lipid Res Unit, Ste Foy, PQ G1V 4G5, Canada

[6] Univ Paris 05, Inst Cochin, CNRS, UMR 8104, F-75014 Paris, France

[7] INSERM, U567, F-75014 Paris, France

[8] Univ Melbourne, St Vincents Inst Med Res, Fitzroy, Vic 3065, Australia

[9] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA

[10] USAF, Res Lab, Human Effectiveness Directorate, Dayton, OH 45433 USA

来源：

CELL METABOLISM | 2010年 / 11卷 / 05期

基金：

英国医学研究理事会; 加拿大健康研究院; 澳大利亚研究理事会; 美国国家卫生研究院;

关键词：

ACTIVATED PROTEIN-KINASE; MAMMALIAN TARGET; CELL-GROWTH; AMINO-ACIDS; INSULIN-RESISTANCE; TUMOR SUPPRESSION; SKELETAL-MUSCLE; S6; KINASE; COMPLEX; RAPTOR;

D O I：

10.1016/j.cmet.2010.03.014

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.

引用

页码：390 / 401

页数：12

共 63 条

[31] 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments [J].