Changes of Glycolytic Pathway in Response to Efficient Inhibition of EGFR Signaling in Non-small Cell Lung Cancer (NSCLC) (Abstract in rivista)

Type
Label
  • Changes of Glycolytic Pathway in Response to Efficient Inhibition of EGFR Signaling in Non-small Cell Lung Cancer (NSCLC) (Abstract in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Alternative label
  • De Rosa, V.; Iommelli, F.; Votta, G.; Monti, M.; Ortosecco, G.; Fonti, R.; Mainolfi, C.; Stoppelli, M.; Del Vecchio, S. (2013)
    Changes of Glycolytic Pathway in Response to Efficient Inhibition of EGFR Signaling in Non-small Cell Lung Cancer (NSCLC)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • De Rosa, V.; Iommelli, F.; Votta, G.; Monti, M.; Ortosecco, G.; Fonti, R.; Mainolfi, C.; Stoppelli, M.; Del Vecchio, S. (literal)
Pagina inizio
  • S348 (literal)
Pagina fine
  • S348 (literal)
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  • 40 (literal)
Rivista
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  • 1 (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • Consiglio Nazionale delle Ricerche (CNR); Consiglio Nazionale delle Ricerche (CNR); University of Naples Federico II (literal)
Titolo
  • Changes of Glycolytic Pathway in Response to Efficient Inhibition of EGFR Signaling in Non-small Cell Lung Cancer (NSCLC) (literal)
Abstract
  • To investigate how the glycolytic pathway is affected by the inhibition of EGFR signaling, we selected NSCLC cells that were resistant to erlotinib due to T790M mutation (H1975) or MET amplification (H1993) and treated them with erlotinib (negative control), third generation EGFR TKIs or MET inhibitors (positive controls) so that differential changes of glycolytic pathway could be observed in the same cellular context in response to the efficient inhibition of EGFR signaling. Materials and Methods. To this end H1975 cells were preliminarily tested for GLUT1, GLUT3, Hexokinase (HK) I and II, Pyruvate Kinase (PK) M1 and M2 expression before and after 48-72 h treatment with erlotinib (1?M) and WZ4002 (0.1?M and 1?M) by real time PCR and western blot analysis. In parallel experiments H1993 cells were treated with erlotinib (1?M) and PHA-665,752 (1?M). 18F-FDG uptake and glucose consumption were then determined in untreated and treated cells along with hexokinase activity and PKM2 phosphorylation status. Finally drug-induced changes of glycolytic pathway were compared to the levels of total and phosphorylated forms of EGFR signaling mediators. Results. Effective inhibition of EGFR signaling in H1975 cells treated with WZ4002 was associated with a dramatic reduction of HKII expression and activity, translocation of GLUT3 from membrane to cytosol and reduction of phosphorylated form of PKM2. Accordingly, a parallel decrease of 18FFDG uptake and glucose consumption was observed in response to effective treatment in those cells. No changes of glycolytic pathway were found in H1975 cells after treatment with erlotinib. Similarly, H1993 cells treated with PHA-665,752 showed a strong reduction of HKII expression, phosphorylated form of PKM2, glucose consumption and 18F-FDG uptake whereas only a slight decrease of phosphorylated form of PKM2 was observed after erlotinib treatment. Furthermore the strong reduction of HKII and phosphorylated form of PKM2 were associated with a decrease of P-EGFR or P-MET in treated H1975 and H1993 cells, respectively, along with a reduction of P-AKT, P-ERK and cyclin D1 in both cell lines. The slight reduction of phosphorylated form of PKM2 in erlotinib treated H1993 cells was associated with a decrease of P-EGFR without inhibition of downstream mediators. Conclusion. Early reduction of 18F-FDG uptake in response to efficient inhibition of EGFR signaling mainly occurs through changes in the expression and activity of HKII and phosphorylation status of PKM2. (literal)
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