Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer (614 views visite)
Clin Cancer Res (ISSN: 1078-0432, 1078-0432linking, 1078-0432print), 2015 Nov 15; 21(22): 5110-5120.
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Paper type Tipo di articolo: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 8.738, 5-year impact factor Impact factor a 5 anni: 8.751
Url: Not available. Non disponibile.
Keywords 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,
Affiliations 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.
References Riferimenti:
Not available. Non disponibili.
Clin Cancer Res (ISSN: 1078-0432, 1078-0432linking, 1078-0432print), 2015 Nov 15; 21(22): 5110-5120.
Export to Esporta in BibTeX Export to Esporta in EndNote
Paper type Tipo di articolo: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 8.738, 5-year impact factor Impact factor a 5 anni: 8.751
Url: Not available. Non disponibile.
Keywords 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,
Affiliations 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.
References Riferimenti:
Not available. Non disponibili.
Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer
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.
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.
Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer
| ▼ Translational Molecular Imaging in Cancer |
| ▼ Molecular imaging for personalized therapy in oncology |
Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer
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Impact Factor: 8.722
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Oppermann S, Schrader FC, Elsasser K, Dolga AM, Kraus AL, Doti N, Wegscheid-Gerlach C, Schlitzer M, Culmsee C
* Novel N-Phenyl-Substituted Thiazolidinediones Protect Neural Cells against Glutamate- and tBid-Induced Toxicity (488 visite)
J Pharmacol Exp Ther (ISSN: 0022-3565, 1521-0103), 2014 Sep; 350(2): 273-289.
Impact Factor: 3.972
Dettagli Esporta in BibTeX Esporta in EndNote
Pedicini P, Strigari L, Benassi M, Caivano R, Fiorentino A, Nappi A, Salvatore M, Storto G
* Critical dose and toxicity index of organs at risk in radiotherapy: analyzing the calculated effects of modified dose fractionation in non-small cell lung cancer (423 visite)
Med Dosim (ISSN: 0958-3947, 1873-4022), 2014 Mar; 39(1): 23-30.
Impact Factor: 0.76
Dettagli Esporta in BibTeX Esporta in EndNote
Iommelli F, De Rosa V, Fonti R, Del Vecchio S
* Molecular Imaging For Detection Of Sensitivity And Resistance To Egfr Tyrosine Kinase Inhibitors In Non-Small Cell Lung Cancer (266 visite)
Clin Transl Imaging (ISSN: 2281-5872print, 2281-7565online), 2014 Feb 20; 2(1): 43-53.
Impact Factor: 0
Dettagli Esporta in BibTeX Esporta in EndNote
Sorriento D, Pascale AV, Finelli R, Carillo AL, Annunziata R, Trimarco B, Iaccarino G
* Targeting mitochondria as therapeutic strategy for metabolic disorders (511 visite)
Sci World J The Scientific World Journal (ISSN: 1537-744x), 2014; 2014: N/D-N/D.
Impact Factor: 1.219
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Severino V, Alessio N, Farina A, Sandomenico A, Cipollaro M, Peluso G, Galderisi U, Chambery A
* Insulin-like growth factor binding proteins 4 and 7 released by senescent cells promote premature senescence in mesenchymal stem cells (424 visite)
Cell Death & (ISSN: 2041-4889, 2041-4889electronic), 2013 Nov 7; 4(11): e911-e911.
Impact Factor: 5.177
Dettagli Esporta in BibTeX Esporta in EndNote
Iommelli F, De Rosa V, Gargiulo S, Panico M, Monti M, Ortosecco G, Greco A, Gramanzini M, Fonti R, Brunetti A, Del Vecchio S
* 18F-FLT PET/CT for Detection of Functional Cross-talk between MET and EGFR in Non-small Cell Lung Cancer Resistant to EGFR Inhibitors (336 visite)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2013 Oct; 40: N/D-N/D.
Impact Factor: 5.217
Dettagli Esporta in BibTeX Esporta in EndNote
De Rosa V, Iommelli F, Votta G, Monti M, Ortosecco G, Fonti R, Mainolfi C, Stoppelli M, Del Vecchio S
* Changes of Glycolytic Pathway in Response to Efficient Inhibition of EGFR Signaling in Non-small Cell Lung Cancer (NSCLC) (241 visite)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2013 Oct; 40: N/D-N/D.
Impact Factor: 5.217
Dettagli Esporta in BibTeX Esporta in EndNote
Zannetti A, Iommelli F, De Rosa V, Nardelli A, Ortosecco G, Del Vecchio S
* Combined Imaging with 18F-FLT PET/CT and 99m-Tc-Hynic-Annexin V SPECT for Personalized Therapy with EGFR Antagonists and Bcl-xL Inhibitors in Non-Small Cell Lung Cancer (355 visite)
European Journal Of Cancer (ISSN: 0959-8049), 2012 Nov; 48: N/D-N/D.
Impact Factor: 5.061
Dettagli Esporta in BibTeX Esporta in EndNote
Zannetti A, Iommelli F, De Rosa V, Salvatore M, Del Vecchio S
* Small animal SPECT with 99m-Tc-Hynic-annexin V for detection of non-small cell lung cancer resistance to EGFR antagonists and its reversal by Bcl-xL inhibitors (377 visite)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2012 Oct; 39: N/D-N/D.
Impact Factor: 5.114
Dettagli Esporta in BibTeX Esporta in EndNote
Sandomenico A, Russo A, Palmieri G, Bergamo P, Gogliettino M, Falcigno L, Ruvo M
* Small peptide inhibitors of acetyl-peptide hydrolase having an uncommon mechanism of inhibition and a stable bent conformation (475 visite)
J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2012 Mar 8; 55(5): 2102-2111.
Impact Factor: 5.614
Dettagli Esporta in BibTeX Esporta in EndNote
Zannetti A, Iommelli F, Speranza A, Salvatore M, Del Vecchio S
* 3'-deoxy-3'-18F-fluorothymidine (FLT) PET/CT to guide therapy with epidermal growth factor receptor (EGFR) antagonists and Bcl-xL inhibitors in non-small cell lung cancer (548 visite)
J Nucl Med (ISSN: 0161-5505, 1535-5667, 1535-5667electronic), 2012 Mar 1; 53(3): 443-450.
Impact Factor: 5.774
Dettagli Esporta in BibTeX Esporta in EndNote
Zannetti A, Iommelli F, Speranza A, Salvatore M, Del Vecchio S
* 3'-deoxy-3'-18F-fluorothymidine PET/CT to guide therapy with epidermal growth factor receptor antagonists and Bcl-xL inhibitors in non-small cell lung cancer (450 visite)
J Nucl Med (ISSN: 1535-5667, 0161-5505, 1535-5667electronic), 2012 Mar 1; 53(3): 443-450.
Impact Factor: 5.774
Dettagli Esporta in BibTeX Esporta in EndNote
Zannetti A, Iommelli F, Fonti R, Papaccioli A, Sommella J, Lettieri A, Pirozzi G, Bianco R, Tortora G, Salvatore M, Del Vecchio S
* Gefitinib induction of in vivo detectable signals by Bcl-2/Bcl-xL modulation of inositol trisphosphate receptor type (484 visite)
Clin Cancer Res (ISSN: 1078-0432, 1078-0432linking, 1078-0432print), 2008 Aug 15; 14(16): 5209-5219.
Impact Factor: 6.488
Dettagli Esporta in BibTeX Esporta in EndNote
Sinibaldi F, Fiorucci L, Patriarca A, Lauceri R, Ferri T, Coletta M, Santucci R
* Insights into cytochrome c-cardiolipin interaction. Role played by ionic strength (330 visite)
Biochemistry (ISSN: 0006-2960, 1520-4995, 1520-4995electronic), 2008 Jul 1; 47(26): 6928-6935.
Impact Factor: 3.379
Dettagli Esporta in BibTeX Esporta in EndNote
Atlante A, Amadoro G, Bobba A, de Bari L, Corsetti V, Pappalardo G, Marra E, Calissano P, Passarella S
* A peptide containing residues 26-44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator (455 visite)
Bba-Gen Subjects (ISSN: 0005-2728, 0006-3002print, 0006-3002linking), 2008; 1777(10): 1289-1300.
Impact Factor: 4.447
Dettagli Esporta in BibTeX Esporta in EndNote
30 Records (22 escludendo Abstract e Conferenze).
Impact factor totale: 127.633 (85.544 escludendo Abstract e Conferenze).
Impact factor a 5 anni totale: 109.592 (69.373 escludendo Abstract e Conferenze).
Last modified by Ultima modifica di Marco Comerci on in data Sunday 12 July 2020, 13:14:48
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