Cancer research (Chicago, Ill.), 2011-06, Vol.71 (11), p.3932-3940
2011
Details
- Autor(en) / Beteiligte
- Titel
- Erlotinib-Mediated Inhibition of EGFR Signaling Induces Metabolic Oxidative Stress through NOX4
- Ist Teil von
- Cancer research (Chicago, Ill.), 2011-06, Vol.71 (11), p.3932-3940
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Redox regulation of epidermal growth factor receptor (EGFR) signaling helps protect cells against oxidative stress. In this study, we investigated whether the cytotoxicity of an EGFR tyrosine kinase inhibitor, erlotinib (ERL), was mediated by induction of oxidative stress in human head and neck cancer (HNSCC) cells. ERL elicited cytotoxicity in vitro and in vivo while increasing a panel of oxidative stress parameters which were all reversible by the antioxidant N-acetyl cysteine. Knockdown of EGFR by using siRNA similarly increased these oxidative stress parameters. Overexpression of mitochondrial targeted catalase but not superoxide dismutase reversed ERL-induced cytotoxicity. Consistent with a general role for NADPH oxidase (NOX) enzymes in ERL-induced oxidative stress, ERL-induced cytotoxicity was reversed by diphenylene iodonium, a NOX complex inhibitor. ERL reduced the expression of NOX1, NOX2, and NOX5 but induced the expression of NOX4. Knockdown of NOX4 by using siRNA protected HNSCC cells from ERL-induced cytotoxicity and oxidative stress. Our findings support the concept that ERL-induced cytotoxicity is based on a specific mechanism of oxidative stress mediated by hydrogen peroxide production through NOX4 signaling.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-10-3425Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3217301
- Format
- –
- Schlagworte
- Animals, Antineoplastic agents, Biological and medical sciences, Carcinoma, Squamous Cell - drug therapy, Carcinoma, Squamous Cell - metabolism, Carcinoma, Squamous Cell - pathology, Cell Cycle - drug effects, Cell Cycle - genetics, Cell Growth Processes - drug effects, Cell Survival - drug effects, Cell Survival - genetics, Cells, Cultured, Erlotinib Hydrochloride, Female, Gene Knockdown Techniques, Head and Neck Neoplasms - drug therapy, Head and Neck Neoplasms - metabolism, Head and Neck Neoplasms - pathology, Humans, Medical sciences, Mice, Mice, Nude, NADPH Oxidase 4, NADPH Oxidases - antagonists & inhibitors, NADPH Oxidases - metabolism, Oxidative Stress - drug effects, Pharmacology. Drug treatments, Protein Kinase Inhibitors - pharmacology, Quinazolines - pharmacology, Reactive Oxygen Species - metabolism, Receptor, Epidermal Growth Factor - antagonists & inhibitors, Receptor, Epidermal Growth Factor - biosynthesis, Receptor, Epidermal Growth Factor - genetics, Receptor, Epidermal Growth Factor - metabolism, Signal Transduction - drug effects, Transfection, Tumors, Xenograft Model Antitumor Assays