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.
Highlights
epidermal growth factor receptor (EGFR) signaling maintains aerobic glycolysis, but the molecular mechanism is still undefined
We confirmed that the HCC827 and PC-9 cell lines were highly sensitive to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib (Fig. 1, A and B), with IC50 values in the nanomolar range compared with the erlotinib-resistant H1975 (Fig. 1C)
We showed that treatment with TKIs to EGFR, namely gefitinib and erlotinib, repressed aerobic glycolysis in EGFR-mutant lung adenocarcinoma (LAD) cells [11]
Summary
EGFR signaling maintains aerobic glycolysis, but the molecular mechanism is still undefined. We have shown previously that mutant EGFR signaling maintains up-regulated aerobic glycolysis, PPP, and de novo pyrimidine biosynthesis [11] In this scenario, the tyrosine kinase activity of EGFR is dysregulated by gene mutations that lead to aberrant EGFR signaling via the RAS/MEK/ERK and PI3K/AKT/mTOR pathways [8, 9]. Of these two pathways, the PI3K/AKT/mTOR signaling axis plays a more critical role in regulating glycolysis in EGFR-mutated LAD and appears to facilitate the proper localization of the glucose transporter GLUT1. Suppression of GLUT1 after blocking with siRNA resulted in decreased lactate production and cell proliferation in EGFR-mutated LAD These findings indicate that the PI3K/AKT/mTOR pathway is responsible for aerobic glycolysis by regulating GLUT1 localization in EGFRmutated LAD
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