Molecular mechanisms of decreased aerobic glycolysis in non-small lung cancer treated with EGFR tyrosine kinase inhibitors. European Society for Molecular Imaging Meeting
| Autor: | De Rosa Viviana, Iommelli Francesca, Monti Marcello, Votta Giuseppina, Fonti Rosa, Stoppelli Maria Patrizia, Del Vecchio Silvana |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Zdroj: | European Molecular Imaging Meeting, Antwerp, 4-6/06/2014 info:cnr-pdr/source/autori:De Rosa Viviana, Iommelli Francesca, Monti Marcello, Votta Giuseppina, Fonti Rosa, Stoppelli Maria Patrizia, Del Vecchio Silvana/congresso_nome:European Molecular Imaging Meeting/congresso_luogo:Antwerp/congresso_data:4-6%2F06%2F2014/anno:2014/pagina_da:/pagina_a:/intervallo_pagine |
| Popis: | Introduction. Cancer cells have distinct energy metabolism that highly depends on glycolysis instead of mitochondrial oxidative phosphorylation alone. The Warburg effect or aerobic glycolysis is indeed considered a hallmark of cancer. Glucose consumption is regulated by many biochemical pathways including mitogenic signaling through Tyrosine Kinase Receptors such as EGFR. Previous clinical studies reported that NSCLC patients that benefit from treatment with EGFR inhibitors show a prompt reduction of 18F-FDG uptake at early time points. Here we investigate the molecular mechanisms underlying the early reduction of 18F-FDG uptake in NSCLC after treatment with a panel of EGFR tyrosine kinase inhibitors (TKIs) including those designed to overcome EGFR resistance to EGFR TKIs. Methods. Efficient inhibition of EGFR signaling was achieved in sensitive NSCLC cell lines using erlotinib whereas resistant NSCLC cell lines were treated with third generation EGFR TKIs or MET inhibitors depending on the mechanism of resistance. Firstly, NSCLC cells were tested for the effects of several inhibitors on EGFR downstream pathway. Moreover, levels of total and phosphorylated forms of EGFR signaling mediators were compared to drug-induced changes of glycolytic pathway. Finally, 18F-FDG uptake and glucose consumption were then determined in untreated and treated cells along with hexokinase activity and PKM2 phosphorylation status. Results. Effective inhibition of EGFR signaling in all 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 the strong reduction of HKII and phosphorylated form of PKM2 were associated with a decrease of p-EGFR or p-MET along with a reduction of p-AKT, p-ERK 1/2 and cyclin D1 in treated cells. 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. Acknowledgment/References: This work was supported by MERIT-Medical Research in Italy and AIRC, Associazione Italiana per la Ricerca sul Cancro. |
| Databáze: | OpenAIRE |
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