title: Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4.
abstract: 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.
authors.affiliation: Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Orcutt
authors.forename: Arlene D
authors.initials: AD
authors.lastname: Parsons
authors.forename: Zita A
authors.initials: ZA
authors.lastname: Sibenaller
authors.forename: Peter M
authors.initials: PM
authors.lastname: Scarbrough
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zhu
authors.forename: Arya
authors.initials: A
authors.lastname: Sobhakumari
authors.forename: Werner W
authors.initials: WW
authors.lastname: Wilke
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kalen
authors.forename: Prabhat
authors.initials: P
authors.lastname: Goswami
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Miller
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Andrean L
authors.initials: AL
authors.lastname: Simons
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017382:Reactive Oxygen Species; D000069347:Erlotinib Hydrochloride; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D066246:ErbB Receptors