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.
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.
['Makinoshima|Hideki|H|', 'Takita|Masahiro|M|', 'Saruwatari|Koichi|K|', 'Umemura|Shigeki|S|', 'Obata|Yuuki|Y|', 'Ishii|Genichiro|G|', 'Matsumoto|Shingo|S|', 'Sugiyama|Eri|E|', 'Ochiai|Atsushi|A|', 'Abe|Ryo|R|', 'Goto|Koichi|K|', 'Esumi|Hiroyasu|H|', 'Tsuchihara|Katsuya|K|']
D000230:Adenocarcinoma D000077192:Adenocarcinoma of Lung D000332:Aerobiosis D045744:Cell Line, Tumor D049109:Cell Proliferation D066246:ErbB Receptors D018773:Genes, erbB-1 D051272:Glucose Transporter Type 1 D006019:Glycolysis D006801:Humans D019344:Lactic Acid D008175:Lung Neoplasms D055432:Metabolomics D009154:Mutation D010427:Pentose Phosphate Pathway D058539:Phosphatidylinositol 3-Kinase D010766:Phosphorylation D051057:Proto-Oncogene Proteins c-akt D034622:RNA Interference D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases
glycolysis glucose transport epidermal growth factor receptor (EGFR) mammalian target of rapamycin (mTOR) metabolomics lung cancer phosphatidylinositol 3-kinase (PI3K)