Erlotinib-Mediated Inhibition of EGFR Signaling Induces Metabolic Oxidative Stress through NOX4

Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242, USA.
Cancer Research (Impact Factor: 9.33). 06/2011; 71(11):3932-40. DOI: 10.1158/0008-5472.CAN-10-3425
Source: PubMed


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.

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Available from: Francis J Miller, Oct 04, 2015
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    • "Erlotinib is a selective reversible inhibitor of the EGFR tyrosine kinase [9]. It inhibits autophosphorylation through binding to the adenosine triphosphate binding site of the receptor [9] and subsequently induces cytotoxicity in cancer cells through induction of reactive oxygen species [10]. It is FDA approved in the United States for the treatment of advanced non-small cell lung cancer and pancreatic cancer [11], [12]. "
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