title: Signaling through the Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Axis Is Responsible for Aerobic Glycolysis mediated by Glucose Transporter in Epidermal Growth Factor Receptor (EGFR)-mutated Lung Adenocarcinoma.
abstract: Oncogenic epidermal growth factor receptor (EGFR) signaling plays an important role in regulating global metabolic pathways, including aerobic glycolysis, the pentose phosphate pathway (PPP), and pyrimidine biosynthesis. However, the molecular mechanism by which EGFR signaling regulates cancer cell metabolism is still unclear. To elucidate how EGFR signaling is linked to metabolic activity, we investigated the involvement of the RAS/MEK/ERK and PI3K/AKT/mammalian target of rapamycin (mTOR) pathways on metabolic alteration in lung adenocarcinoma (LAD) cell lines with activating EGFR mutations. Although MEK inhibition did not alter lactate production and the extracellular acidification rate, PI3K/mTOR inhibitors significantly suppressed glycolysis in EGFR-mutant LAD cells. Moreover, a comprehensive metabolomics analysis revealed that the levels of glucose 6-phosphate and 6-phosphogluconate as early metabolites in glycolysis and PPP were decreased after inhibition of the PI3K/AKT/mTOR pathway, suggesting a link between PI3K signaling and the proper function of glucose transporters or hexokinases in glycolysis. Indeed, PI3K/mTOR inhibition effectively suppressed membrane localization of facilitative glucose transporter 1 (GLUT1), which, instead, accumulated in the cytoplasm. Finally, aerobic glycolysis and cell proliferation were down-regulated when GLUT1 gene expression was suppressed by RNAi. Taken together, these results suggest that PI3K/AKT/mTOR signaling is indispensable for the regulation of aerobic glycolysis in EGFR-mutated LAD cells.
authors.affiliation: From the Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan, hmakinos@east.ncc.go.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makinoshima
authors.affiliation: From the Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan, the Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takita
authors.affiliation: the Thoracic Oncology and.
authors.forename: Koichi
authors.initials: K
authors.lastname: Saruwatari
authors.affiliation: the Thoracic Oncology and.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Umemura
authors.affiliation: the Divisions of Immunobiology and.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Obata
authors.affiliation: Pathology Divisions, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan, and.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
authors.affiliation: From the Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan, the Thoracic Oncology and.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: the Thoracic Oncology and.
authors.forename: Eri
authors.initials: E
authors.lastname: Sugiyama
authors.affiliation: Pathology Divisions, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan, and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: the Divisions of Immunobiology and.
authors.forename: Ryo
authors.initials: R
authors.lastname: Abe
authors.affiliation: the Thoracic Oncology and.
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.affiliation: Clinical Research, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Esumi
authors.affiliation: From the Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan, the Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000332:Aerobiosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D018773:Genes, erbB-1; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D055432:Metabolomics; D009154:Mutation; D010427:Pentose Phosphate Pathway; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; C495677:SLC2A1 protein, human; D019344:Lactic Acid; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: epidermal growth factor receptor (EGFR); glucose transport; glycolysis; lung cancer; mammalian target of rapamycin (mTOR); metabolomics; phosphatidylinositol 3-kinase (PI3K)