The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake.
Human cancers often display an avidity for glucose, a feature that is exploited in clinical staging and response monitoring by using (18)F-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.
Department of Surgery, Box 356410, University of Washington, 1959 NE Pacific, Seattle, WA 98195, USA.
Xiuyun
X
Jiang
Heidi
H
Kenerson
Lauri
L
Aicher
Robert
R
Miyaoka
Janet
J
Eary
John
J
Bissler
Raymond S
RS
Yeung
D000293:Adolescent; D000328:Adult; D018207:Angiomyolipoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D046912:Multiprotein Complexes; D049268:Positron-Emission Tomography; D021381:Protein Transport; D011506:Proteins; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000502:physiology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
C519510:Crtc1 protein, rat; D051246:Glucose Transport Proteins, Facilitative; D051272:Glucose Transporter Type 1; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D046912:Multiprotein Complexes; D011506:Proteins; D019275:Radiopharmaceuticals; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D019788:Fluorodeoxyglucose F18; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose