Early reduction of 18F-FDG uptake in non-small lung cancer treated with EGFR tyrosine kinase inhibitors reflects reversal of Warburg effect and reactivation of oxidative phosphorylation. (Abstract in rivista)

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Label
  • Early reduction of 18F-FDG uptake in non-small lung cancer treated with EGFR tyrosine kinase inhibitors reflects reversal of Warburg effect and reactivation of oxidative phosphorylation. (Abstract in rivista) (literal)
Anno
  • 2014-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1007/s00259-014-2901-9 (literal)
Alternative label
  • De Rosa Viviana, Iommelli Francesca, Monti Marcello, Fonti Rosa, Del Vecchio Silvana (2014)
    Early reduction of 18F-FDG uptake in non-small lung cancer treated with EGFR tyrosine kinase inhibitors reflects reversal of Warburg effect and reactivation of oxidative phosphorylation.
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • De Rosa Viviana, Iommelli Francesca, Monti Marcello, Fonti Rosa, Del Vecchio Silvana (literal)
Pagina inizio
  • S248 (literal)
Pagina fine
  • S248 (literal)
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  • 41 (literal)
Rivista
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  • Institute of Biostructures and Bioimages, National Research Council; Department of Advanced Biomedical Sciences, University of Naples \"Federico II\", Naples, Italy (literal)
Titolo
  • Early reduction of 18F-FDG uptake in non-small lung cancer treated with EGFR tyrosine kinase inhibitors reflects reversal of Warburg effect and reactivation of oxidative phosphorylation. (literal)
Abstract
  • Aim: Previous clinical studies reported that non-small cell lung cancer (NSCLC) patients that benefit from treatment with EGFR inhibitors show a prompt reduction of 18F-FDG uptake at early time points. We investigated the molecular mechanisms underlying the early reduction of 18F-FDG uptake in NSCLC after treatment with EGFR tyrosine kinase inhibitors (TKIs) and tested whether the inhibition of EGFR pathway may revert the Warburg effect thus restoring mitochondrial oxidative phosphorylation in tumor cells. Methods: Efficient inhibition of EGFR signaling was achieved in sensitive HCC827 NSCLC cell lines using erlotinib whereas resistant NSCLC cell lines (H1975 and H1993) were treated with third generation EGFR TKI (WZ4002) and MET inhibitors (PHA-665,752 or crizotinib) depending on the mechanism of resistance. NSCLC cells were tested for the effects of several inhibitors on EGFR downstream pathway and glycolytic cascade. In particular levels of GLUT1, GLUT3, Hexokinase (HK) I and II, Pyruvate Kinase (PK) M1 and M2 were determined before and after 48-72 h treatment with EGFR TKIs by western blot analysis. Furthermore 18F-FDG uptake, glucose consumption, lactate secretion and ATP production were determined in untreated and treated cells along with the levels of several mitochondrial complexes involved in oxidative phosphorylation. In parallel, nude mice bearing NSCLCs were subjected to imaging studies using 18F-FDG PET/CT before and after treatment with EGFR inhibitors. At the end of imaging studies, tumors were removed and analysed for glycolytic enzymes, mitochondrial proteins and signaling cascade by western blot analysis. Results: Effective inhibition of EGFR signaling in NSCLC cell lines treated with appropriate inhibitors 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 18F-FDG uptake and glucose consumption was observed in response to effective treatment in those cells. Furthermore a concomitant reduction of lactate secretion, an increase of ATP production and an increase of the expression levels of several mitochondrial complexes were also observed in response to effective inhibition of EGFR pathway. In agreement with in vitro findings, early reduction of 18F-FDG uptake in tumor-bearing animals treated with appropriate inhibitors was associated with reduction of HKII and phosphorylated form of PKM2 whereas levels of several mitochondrial complexes involved in oxidative phosphorylation increased after treatment. Conclusion: Early reduction of 18F-FDG uptake in non-small lung cancer treated with EGFR tyrosine kinase inhibitors indicates reversal of Warburg effect and reactivation of oxidative phosphorylation. (literal)
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