Journal article
NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells
Toxicology and applied pharmacology, Vol.272(3), pp.736-745
11/01/2013
DOI: 10.1016/j.taap.2013.07.013
PMCID: PMC3808873
PMID: 23917044
Abstract
Most head and neck squamous cell carcinomas (HNSCCs) overexpress epidermal growth factor receptor (EGFR) and EGFR inhibitors are routinely used in the treatment of HNSCC. However, many HNSCC tumors do not respond or become refractory to EGFR inhibitors. Autophagy, which is a stress-induced cellular self-degradation process, has been reported to reduce the efficacy of chemotherapy in various disease models. The purpose of this study is to determine if the efficacy of the EGFR inhibitor erlotinib is reduced by activation of autophagy via NOX4-mediated oxidative stress in HNSCC cells. Erlotinib induced the expression of the autophagy marker LC3B-II and autophagosome formation in FaDu and Cal-27 cells. Inhibition of autophagy by chloroquine and knockdown of autophagy pathway genes Beclin-1 and Atg5 sensitized both cell lines to erlotinib-induced cytotoxicity, suggesting that autophagy may serve as a protective mechanism. Treatment with catalase (CAT) and diphenylene iodonium (DPI) in the presence of erlotinib suppressed the increase in LC3B-II expression in FaDu and Cal-27 cells. Erlotinib increased NOX4 mRNA and protein expression by increasing its promoter activity and mRNA stability in FaDu cells. Knockdown of NOX4 using adenoviral siNOX4 partially suppressed erlotinib-induced LC3B-II expression, while overexpression of NOX4 increased expression of LC3B-II. These studies suggest that erlotinib may activate autophagy in HNSCC cells as a pro-survival mechanism, and NOX4 may play a role in mediating this effect.
•Erlotinib increased LC3B-II and autophagosome formation in HNSCC cells.•Inhibition of autophagy sensitized HNSCC cells to erlotinib.•Erlotinib increased NOX4 promoter and 3′UTR luciferase activity.•Manipulating NOX4 decreases or increases autophagy.
Details
- Title: Subtitle
- NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells
- Creators
- Arya Sobhakumari - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USABrandon M Schickling - Department of Internal Medicine, The University of Iowa, Iowa City, IA, USALaurie Love-Homan - Department of Pathology, The University of Iowa, Iowa City, IA, USAAyanna Raeburn - Department of Pathology, The University of Iowa, Iowa City, IA, USAElise V.M Fletcher - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USAAdam J Case - Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USAFrederick E Domann - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USAFrancis J Miller - Department of Internal Medicine, The University of Iowa, Iowa City, IA, USAAndrean L Simons - Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Toxicology and applied pharmacology, Vol.272(3), pp.736-745
- DOI
- 10.1016/j.taap.2013.07.013
- PMID
- 23917044
- PMCID
- PMC3808873
- NLM abbreviation
- Toxicol Appl Pharmacol
- ISSN
- 0041-008X
- eISSN
- 1096-0333
- Publisher
- Elsevier Inc
- Grant note
- name: Department of Pathology; name: NIH, award: K01CA134941; DOI: 10.13039/100000048, name: American Cancer Society; name: Holden Comprehensive Cancer Center at the University of Iowa, award: IRG-77-004-34
- Language
- English
- Date published
- 11/01/2013
- Academic Unit
- Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Surgery; Radiation Oncology; Obstetrics and Gynecology
- Record Identifier
- 9984046910102771
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