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Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4.

Publication ,  Journal Article
Orcutt, KP; Parsons, AD; Sibenaller, ZA; Scarbrough, PM; Zhu, Y; Sobhakumari, A; Wilke, WW; Kalen, AL; Goswami, P; Miller, FJ; Spitz, DR; Simons, AL
Published in: Cancer Res
June 1, 2011

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.

Duke Scholars

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

June 1, 2011

Volume

71

Issue

11

Start / End Page

3932 / 3940

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transfection
  • Signal Transduction
  • Reactive Oxygen Species
  • Quinazolines
  • Protein Kinase Inhibitors
  • Oxidative Stress
  • Oncology & Carcinogenesis
  • NADPH Oxidases
  • NADPH Oxidase 4
 

Citation

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Orcutt, K. P., Parsons, A. D., Sibenaller, Z. A., Scarbrough, P. M., Zhu, Y., Sobhakumari, A., … Simons, A. L. (2011). Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res, 71(11), 3932–3940. https://doi.org/10.1158/0008-5472.CAN-10-3425
Orcutt, Kevin P., Arlene D. Parsons, Zita A. Sibenaller, Peter M. Scarbrough, Yueming Zhu, Arya Sobhakumari, Werner W. Wilke, et al. “Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4.Cancer Res 71, no. 11 (June 1, 2011): 3932–40. https://doi.org/10.1158/0008-5472.CAN-10-3425.
Orcutt KP, Parsons AD, Sibenaller ZA, Scarbrough PM, Zhu Y, Sobhakumari A, et al. Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res. 2011 Jun 1;71(11):3932–40.
Orcutt, Kevin P., et al. “Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4.Cancer Res, vol. 71, no. 11, June 2011, pp. 3932–40. Pubmed, doi:10.1158/0008-5472.CAN-10-3425.
Orcutt KP, Parsons AD, Sibenaller ZA, Scarbrough PM, Zhu Y, Sobhakumari A, Wilke WW, Kalen AL, Goswami P, Miller FJ, Spitz DR, Simons AL. Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res. 2011 Jun 1;71(11):3932–3940.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

June 1, 2011

Volume

71

Issue

11

Start / End Page

3932 / 3940

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Transfection
  • Signal Transduction
  • Reactive Oxygen Species
  • Quinazolines
  • Protein Kinase Inhibitors
  • Oxidative Stress
  • Oncology & Carcinogenesis
  • NADPH Oxidases
  • NADPH Oxidase 4