title: Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma.
abstract: Genetic mutations in tumor cells cause several unique metabolic phenotypes that are critical for cancer cell proliferation. Mutations in the tyrosine kinase epidermal growth factor receptor (EGFR) induce oncogenic addiction in lung adenocarcinoma (LAD). However, the linkage between oncogenic mutated EGFR and cancer cell metabolism has not yet been clearly elucidated. Here we show that EGFR signaling plays an important role in aerobic glycolysis in EGFR-mutated LAD cells. EGFR-tyrosine kinase inhibitors (TKIs) decreased lactate production, glucose consumption, and the glucose-induced extracellular acidification rate (ECAR), indicating that EGFR signaling maintained aerobic glycolysis in LAD cells. Metabolomic analysis revealed that metabolites in the glycolysis, pentose phosphate pathway (PPP), pyrimidine biosynthesis, and redox metabolism were significantly decreased after treatment of LAD cells with EGFRTKI. On a molecular basis, the glucose transport carried out by glucose transporter 3 (GLUT3) was downregulated in TKI-sensitive LAD cells. Moreover, EGFR signaling activated carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the first step in de novo pyrimidine synthesis. We conclude that EGFR signaling regulates the global metabolic pathway in EGFR-mutated LAD cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, which is an attractive target for the development of more effective targeted therapies to treat patients with EGFR-mutated LAD.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makinoshima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takita
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yagishita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Owada
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Esumi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001221:Aspartate Carbamoyltransferase / Q000235:genetics / Q000378:metabolism; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004080:Dihydroorotase / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D051274:Glucose Transporter Type 3; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010427:Pentose Phosphate Pathway / Q000235:genetics; D015398:Signal Transduction
chemical_list: C033626:CAD trifunctional enzyme; D051274:Glucose Transporter Type 3; D009363:Neoplasm Proteins; C495687:SLC2A3 protein, human; D019344:Lactic Acid; D004815:Epidermal Growth Factor; D001221:Aspartate Carbamoyltransferase; C512478:EGFR protein, human; D066246:ErbB Receptors; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D005947:Glucose