The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake

Xiuyun Jiang, Heidi Kenerson, Lauri Aicher, Robert Miyaoka, Janet Eary, John Bissler, Raymond S. Yeung

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Human cancers often display an avidity for glucose, a feature that is exploited in clinical staging and response monitoring by using 18F-fluoro-deoxyglucose (FDG) positron emission tomography. Determinants of FDG accumulation include tumor blood flow, glucose transport, and glycolytic rate, but the underlying molecular mechanisms are incompletely understood. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin complex (mTORC) 1 pathway has been implicated in this process via the hypoxia-inducible factor alpha-dependent expression of vascular endothelial growth factor and glycolytic enzymes. Thus, we predicted that tumors with elevated mTORC1 activity would be accompanied by high FDG uptake. We tested this hypothesis in eight renal angiomyolipomas in which the loss of tuberous sclerosis complex (TSC) 1/2 function gave rise to constitutive mTORC1 activation. Surprisingly, these tumors displayed low FDG uptake on positron emission tomography. Exploring the underlying mechanisms in vitro revealed that Tsc2 regulates the membrane localization of the glucose transporter proteins (Glut)1, Glut2, and Glut4, and, therefore, glucose uptake. Down-regulation of cytoplasmic linker protein 170, an mTOR effector, rescued Glut4 trafficking in Tsc2-/- cells, whereas up-regulation of Akt activity in these cells was insufficient to redistribute Glut4 to the plasma membrane. The effect of mTORC1 on glucose uptake was confirmed using a liver-specific Tsc1- deletion mouse model in which FDG uptake was reduced in the livers of mutant mice compared with wild-type controls. Together, these data show that mTORC1 activity is insufficient for increased glycolysis in tumors and that constitutive mTOR activity negatively regulates glucose transporter trafficking.

Original languageEnglish (US)
Pages (from-to)1748-1756
Number of pages9
JournalAmerican Journal of Pathology
Volume172
Issue number6
DOIs
StatePublished - Jan 1 2008

Fingerprint

Tuberous Sclerosis
Facilitative Glucose Transport Proteins
Deoxyglucose
Glucose
Neoplasms
Positron-Emission Tomography
Angiomyolipoma
1-Phosphatidylinositol 4-Kinase
Liver
Glycolysis
Vascular Endothelial Growth Factor A
Blood Glucose
Up-Regulation
Down-Regulation
Cell Membrane
mechanistic target of rapamycin complex 1
Kidney
Membranes
Enzymes
Proteins

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake. / Jiang, Xiuyun; Kenerson, Heidi; Aicher, Lauri; Miyaoka, Robert; Eary, Janet; Bissler, John; Yeung, Raymond S.

In: American Journal of Pathology, Vol. 172, No. 6, 01.01.2008, p. 1748-1756.

Research output: Contribution to journalArticle

Jiang, Xiuyun ; Kenerson, Heidi ; Aicher, Lauri ; Miyaoka, Robert ; Eary, Janet ; Bissler, John ; Yeung, Raymond S. / The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake. In: American Journal of Pathology. 2008 ; Vol. 172, No. 6. pp. 1748-1756.
@article{c3d7a86d610548708eb1cbfbe6c15882,
title = "The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake",
abstract = "Human cancers often display an avidity for glucose, a feature that is exploited in clinical staging and response monitoring by using 18F-fluoro-deoxyglucose (FDG) positron emission tomography. Determinants of FDG accumulation include tumor blood flow, glucose transport, and glycolytic rate, but the underlying molecular mechanisms are incompletely understood. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin complex (mTORC) 1 pathway has been implicated in this process via the hypoxia-inducible factor alpha-dependent expression of vascular endothelial growth factor and glycolytic enzymes. Thus, we predicted that tumors with elevated mTORC1 activity would be accompanied by high FDG uptake. We tested this hypothesis in eight renal angiomyolipomas in which the loss of tuberous sclerosis complex (TSC) 1/2 function gave rise to constitutive mTORC1 activation. Surprisingly, these tumors displayed low FDG uptake on positron emission tomography. Exploring the underlying mechanisms in vitro revealed that Tsc2 regulates the membrane localization of the glucose transporter proteins (Glut)1, Glut2, and Glut4, and, therefore, glucose uptake. Down-regulation of cytoplasmic linker protein 170, an mTOR effector, rescued Glut4 trafficking in Tsc2-/- cells, whereas up-regulation of Akt activity in these cells was insufficient to redistribute Glut4 to the plasma membrane. The effect of mTORC1 on glucose uptake was confirmed using a liver-specific Tsc1- deletion mouse model in which FDG uptake was reduced in the livers of mutant mice compared with wild-type controls. Together, these data show that mTORC1 activity is insufficient for increased glycolysis in tumors and that constitutive mTOR activity negatively regulates glucose transporter trafficking.",
author = "Xiuyun Jiang and Heidi Kenerson and Lauri Aicher and Robert Miyaoka and Janet Eary and John Bissler and Yeung, {Raymond S.}",
year = "2008",
month = "1",
day = "1",
doi = "10.2353/ajpath.2008.070958",
language = "English (US)",
volume = "172",
pages = "1748--1756",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake

AU - Jiang, Xiuyun

AU - Kenerson, Heidi

AU - Aicher, Lauri

AU - Miyaoka, Robert

AU - Eary, Janet

AU - Bissler, John

AU - Yeung, Raymond S.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - Human cancers often display an avidity for glucose, a feature that is exploited in clinical staging and response monitoring by using 18F-fluoro-deoxyglucose (FDG) positron emission tomography. Determinants of FDG accumulation include tumor blood flow, glucose transport, and glycolytic rate, but the underlying molecular mechanisms are incompletely understood. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin complex (mTORC) 1 pathway has been implicated in this process via the hypoxia-inducible factor alpha-dependent expression of vascular endothelial growth factor and glycolytic enzymes. Thus, we predicted that tumors with elevated mTORC1 activity would be accompanied by high FDG uptake. We tested this hypothesis in eight renal angiomyolipomas in which the loss of tuberous sclerosis complex (TSC) 1/2 function gave rise to constitutive mTORC1 activation. Surprisingly, these tumors displayed low FDG uptake on positron emission tomography. Exploring the underlying mechanisms in vitro revealed that Tsc2 regulates the membrane localization of the glucose transporter proteins (Glut)1, Glut2, and Glut4, and, therefore, glucose uptake. Down-regulation of cytoplasmic linker protein 170, an mTOR effector, rescued Glut4 trafficking in Tsc2-/- cells, whereas up-regulation of Akt activity in these cells was insufficient to redistribute Glut4 to the plasma membrane. The effect of mTORC1 on glucose uptake was confirmed using a liver-specific Tsc1- deletion mouse model in which FDG uptake was reduced in the livers of mutant mice compared with wild-type controls. Together, these data show that mTORC1 activity is insufficient for increased glycolysis in tumors and that constitutive mTOR activity negatively regulates glucose transporter trafficking.

AB - Human cancers often display an avidity for glucose, a feature that is exploited in clinical staging and response monitoring by using 18F-fluoro-deoxyglucose (FDG) positron emission tomography. Determinants of FDG accumulation include tumor blood flow, glucose transport, and glycolytic rate, but the underlying molecular mechanisms are incompletely understood. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin complex (mTORC) 1 pathway has been implicated in this process via the hypoxia-inducible factor alpha-dependent expression of vascular endothelial growth factor and glycolytic enzymes. Thus, we predicted that tumors with elevated mTORC1 activity would be accompanied by high FDG uptake. We tested this hypothesis in eight renal angiomyolipomas in which the loss of tuberous sclerosis complex (TSC) 1/2 function gave rise to constitutive mTORC1 activation. Surprisingly, these tumors displayed low FDG uptake on positron emission tomography. Exploring the underlying mechanisms in vitro revealed that Tsc2 regulates the membrane localization of the glucose transporter proteins (Glut)1, Glut2, and Glut4, and, therefore, glucose uptake. Down-regulation of cytoplasmic linker protein 170, an mTOR effector, rescued Glut4 trafficking in Tsc2-/- cells, whereas up-regulation of Akt activity in these cells was insufficient to redistribute Glut4 to the plasma membrane. The effect of mTORC1 on glucose uptake was confirmed using a liver-specific Tsc1- deletion mouse model in which FDG uptake was reduced in the livers of mutant mice compared with wild-type controls. Together, these data show that mTORC1 activity is insufficient for increased glycolysis in tumors and that constitutive mTOR activity negatively regulates glucose transporter trafficking.

UR - http://www.scopus.com/inward/record.url?scp=44849114657&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44849114657&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2008.070958

DO - 10.2353/ajpath.2008.070958

M3 - Article

VL - 172

SP - 1748

EP - 1756

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 6

ER -