Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer
Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer(328 visite) De Rosa V, Iommelli F, Monti M, Fonti R, Votta G, Stoppelli MP, Del Vecchio S
CLIN CANCER RES (ISSN: 1078-0432), 2015 Nov 15; 21(22): 5110-5120.
Tipo di articolo: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 8.738, Impact factor a 5 anni: 8.751
Url: Non disponibile.
Parole chiave: Egfr, Aerobic Glycolysis, Oxidative Phosphorylation, Non-Small Cell Lung Cancer, Animals
, Apoptosis Drug Effects
, Carcinoma, Non-Small-Cell Lung Drug Therapy Genetics Metabolism Pathology
, Cell Line, Tumor
, Cell Proliferation Drug Effects
, Glucose Metabolism
, Humans
, Lactic Acid Metabolism
, Mice
, Mitochondria Drug Effects Metabolism Pathology
, Oxidative Phosphorylation Drug Effects
, Protein Kinase Inhibitors Administration, Dosage
, Proto-Oncogene Proteins C-Met Antagonists, Inhibitors Genetics
, Receptor, Epidermal Growth Factor Antagonists, Signal Transduction Drug Effects
, Xenograft Model Antitumor Assays,
Affiliazioni:
*** IBB - CNR *** Institute of Biostructures and Bioimages, National Research Council, Naples, Italy. Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy. Institute of Genetics and Biophysics, National Research Council, Naples, Italy.
Riferimenti:
Non disponibile.
PURPOSE: One of the hallmarks of cancer cells is the excessive conversion of glucose to lactate under normoxic conditions, also known as the Warburg effect. Here, we tested whether the targeted inhibition of EGFR may revert this effect and reactivate mitochondrial oxidative phosphorylation in non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Sensitive (HCC827) and resistant (H1975 and H1993) NSCLC cells were treated with a panel of EGFR or MET inhibitors, and then tested for changes of EGFR signaling, glycolytic cascade, and mitochondrial function. Silencing of key glycolytic enzymes was then performed with targeted siRNAs. Furthermore, tumor-bearing nude mice treated with EGFR inhibitors were evaluated with (18)F-FDG PET/CT and tumors were analyzed for glycolytic and mitochondrial proteins. RESULTS: Effective inhibition of EGFR signaling in NSCLC cells induced a dramatic reduction of hexokinase II (HKII) and phospho-pyruvate kinase M2 (p-PKM2, Tyr105) levels as well as an upregulation of mitochondrial complexes subunits (OXPHOS). Accordingly, a decreased lactate secretion and increased intracellular ATP levels were also observed in response to EGFR inhibitors. Downregulation of HKII and PKM2 by targeted siRNA transfection did not cause upregulation of OXPHOS but enhanced the effects of EGFR TKIs. Conversely, selective inhibition of AKT and ERK1/2 caused OXPHOS upregulation and glycolysis inhibition, respectively. Similar findings were obtained in tumors from animals treated with appropriate EGFR inhibitors. CONCLUSIONS: Our findings indicate that EGFR inhibitors may reactivate oxidative phosphorylation of cancer cells and provide a mechanistic clue for the rational combination of agents targeting EGFR-dependent proliferation and glucose metabolism in cancer therapy. Clin Cancer Res; 21(22); 5110-20. (c)2015 AACR.
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(47 visite) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 DettagliEsporta in BibTeXEsporta in EndNote
Aloj L, Aurilio M, Rinaldi V, D'Ambrosio L, Tesauro D, Peitl PK, Maina T, Mansi R, Von Guggenberg E, Joosten L, Sosabowski JK, Breeman WA, De Blois E, Koelewijn S, Melis M, Waser B, Beetschen K, Reubi JC, De Jong M * The EEE project(111 visite) Proc Int Cosm Ray Conf Icrc Universidad Nacional Autonoma De Mexico, 2007; 5(HEPART2): 977-980. Impact Factor:0 DettagliEsporta in BibTeXEsporta in EndNote
187 Records (161 escludendo Abstract e Conferenze). Impact factor totale: 576.445 (493.356 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 605.308 (513.678 escludendo Abstract e Conferenze).
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