title: NFκB up-regulation of glucose transporter 3 is essential for hyperactive mammalian target of rapamycin-induced aerobic glycolysis and tumor growth.
abstract: Accumulating evidence indicates that mammalian target of rapamycin (mTOR) exerts a crucial role in aerobic glycolysis and tumorigenesis, but the underlying mechanisms remain largely obscure. Results from Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs) and human cancer cell lines consistently indicate that the expression of glucose transporter 3 (Glut3) is dramatically up-regulated by mTOR. The rapamycin-sensitive mTOR complex 1 (mTORC1), but not the rapamycin-insensitive mTOR complex 2 (mTORC2), was involved in the regulation of Glut3 expression. Moreover, mTORC1 enhances Glut3 expression through the activation of the IKK/NFκB pathway. Depletion of Glut3 led to the suppression of aerobic glycolysis, the inhibition of cell proliferation and colony formation, and the attenuation of the tumorigenic potential of the cells with aberrantly hyper-activated mTORC1 signaling in nude mice. We conclude that Glut3 is a downstream target of mTORC1, and it is critical for oncogenic mTORC1-mediated aerobic glycolysis and tumorigenesis. Hence Glut3 may be a potential target for therapy against cancers caused by the aberrantly activated mTORC1 signaling.
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zha
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology & Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China; Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; Department of nephrology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Keguo
authors.initials: K
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology & Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Chunjia
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; School of Life Sciences, Anhui Medical University, Hefei, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Xianguo
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Anhui Medical University, Hefei, China; Faculty of Health Sciences, University of Macau, Macau, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Di
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medicine, Anhui Medical University, Hefei, China; School of Life Sciences, Anhui Medical University, Hefei, China. Electronic address: zhouhaisheng2000@gmail.com.
authors.forename: Haisheng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Physiology & Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051274:Glucose Transporter Type 3; D046912:Multiprotein Complexes; D016328:NF-kappa B; C495687:SLC2A3 protein, human; C495689:Slc2a3 protein, mouse; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; 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; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Aerobic glycolysis; Glut3; NFκB; Tumorigenesis; mTOR