Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer (782 views)
Clin Cancer Res (ISSN: 1078-0432, 1078-0432linking, 1078-0432print), 2015 Nov 15; 21(22): 5110-5120.
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Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 8.738, 5-year impact factor: 8.751
Url: Not available.
Keywords: 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:
*** 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:
Not available.
Clin Cancer Res (ISSN: 1078-0432, 1078-0432linking, 1078-0432print), 2015 Nov 15; 21(22): 5110-5120.
Export to BibTeX Export to EndNote
Paper type: Journal Article, Research Support, Non-U. S. Gov'T,
Impact factor: 8.738, 5-year impact factor: 8.751
Url: Not available.
Keywords: 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:
*** 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:
Not available.
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
Other filter: ([btitle,keywords] "Aerobic Glycolysis" ...
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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 (4202 views)
Cell Death & (ISSN: 2041-4889, 2041-4889electronic), 2013 Nov 7; 4(11): e911-e911.
Impact Factor: 5.177
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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 (533 views)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2013 Oct; 40: N/D-N/D.
Impact Factor: 5.217
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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) (323 views)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2013 Oct; 40: N/D-N/D.
Impact Factor: 5.217
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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 (547 views)
European Journal Of Cancer (ISSN: 0959-8049), 2012 Nov; 48: N/D-N/D.
Impact Factor: 5.061
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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 (523 views)
Eur J Nucl Med (ISSN: 1619-7070, 1619-7089, 0340-6997), 2012 Oct; 39: N/D-N/D.
Impact Factor: 5.114
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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 (771 views)
J Med Chem (ISSN: 0022-2623, 1520-4804, 0022-2623print), 2012 Mar 8; 55(5): 2102-2111.
Impact Factor: 5.614
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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 (823 views)
J Nucl Med (ISSN: 0161-5505, 1535-5667, 1535-5667electronic), 2012 Mar 1; 53(3): 443-450.
Impact Factor: 5.774
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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 (752 views)
J Nucl Med (ISSN: 1535-5667, 0161-5505, 1535-5667electronic), 2012 Mar 1; 53(3): 443-450.
Impact Factor: 5.774
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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 (736 views)
Clin Cancer Res (ISSN: 1078-0432, 1078-0432linking, 1078-0432print), 2008 Aug 15; 14(16): 5209-5219.
Impact Factor: 6.488
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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 (703 views)
Biochemistry (ISSN: 0006-2960, 1520-4995, 1520-4995electronic), 2008 Jul 1; 47(26): 6928-6935.
Impact Factor: 3.379
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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 (829 views)
Bba-Gen Subjects (ISSN: 0005-2728, 0006-3002print, 0006-3002linking), 2008; 1777(10): 1289-1300.
Impact Factor: 4.447
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30 Records (22 excluding Abstracts).
Total impact factor: 132.84 (90.751 excluding Abstracts).
Total 5 year impact factor: 114.772 (74.553 excluding Abstracts).
Total impact factor: 132.84 (90.751 excluding Abstracts).
Total 5 year impact factor: 114.772 (74.553 excluding Abstracts).
782 views. Last view on Wednesday 15 January 2025, 12:29:47
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