EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC

Elise V M Fletcher; Laurie Love-Homan; Arya Sobhakumari; Charlotte R Feddersen; Adam T Koch; Apollina Goel; Andrean L Simons

doi:10.1158/1541-7786.MCR-13-0187

Back

EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC

Journal article

Open access

Peer reviewed

EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC

Elise V M Fletcher, Laurie Love-Homan, Arya Sobhakumari, Charlotte R Feddersen, Adam T Koch, Apollina Goel and Andrean L Simons

Molecular cancer research, Vol.11(12), pp.1574-1584

12/2013

DOI: 10.1158/1541-7786.MCR-13-0187

PMCID: PMC3869882

PMID: 24048704

Files and links (1)

url

https://doi.org/10.1158/1541-7786.MCR-13-0187View

Published (Version of record) Open Access

Abstract

Chronic inflammation plays a fundamental role in tumor promotion, migration, and invasion. With the use of microarray profiling, a profound increase was observed for those transcripts involved in proinflammatory signaling in epidermal growth factor receptor (EGFR) inhibitor-treated head and neck squamous cell carcinoma (HNSCC) cells as compared with their respective controls. As such, it was hypothesized that EGFR inhibitor efficacy is offset by the proinflammatory response that these therapeutics conjure in HNSCC. Systematic evaluation of the clinical EGFR inhibitors-erlotinib, cetuximab, lapatinib, and panitumumab-revealed increased secretion of proinflammatory cytokines such as interleukins (IL-2, IL-4, IL-6, IL-8), granulocyte-macrophage colony-stimulating factor, TNF-α, and IFN-γ. Mechanistic focus on IL-6 revealed that erlotinib induced a time-dependent increase in IL-6 mRNA and protein expression. Importantly, exogenous IL-6 protected HNSCC cells from erlotinib-induced cytotoxicity, whereas tocilizumab, an IL-6 receptor antagonist, sensitized cells to erlotinib in vitro and in vivo. Inhibitors of NF-κB, p38, and JNK suppressed erlotinib-induced IL-6 expression, suggesting critical roles for NF-κB and MAPK in IL-6 regulation. Furthermore, knockdown of NADPH oxidase 4 (NOX4) suppressed erlotinib-induced proinflammatory cytokine expression. Taken together, these results demonstrate that clinical EGFR inhibitors induce the expression of proinflammatory cytokines via NOX4. The antitumor activity of EGFR inhibitors is reduced by activation of NOX4-mediated proinflammatory pathways in HNSCC.

Erlotinib Hydrochloride

Oligonucleotide Array Sequence Analysis

Carcinoma, Squamous Cell - genetics

Carcinoma, Squamous Cell - metabolism

Humans

Panitumumab

Gene Expression Regulation, Neoplastic

NADPH Oxidases - metabolism

Gene Expression Profiling

Head and Neck Neoplasms - metabolism

Gene Knockdown Techniques

Inflammation - metabolism

Squamous Cell Carcinoma of Head and Neck

Time Factors

Antibodies, Monoclonal, Humanized - pharmacology

NADPH Oxidases - genetics

Lapatinib

Cetuximab

Cytokines - genetics

ErbB Receptors - antagonists & inhibitors

ErbB Receptors - metabolism

Cytokines - metabolism

Antibodies, Monoclonal - pharmacology

Head and Neck Neoplasms - drug therapy

NADPH Oxidase 4

Carcinoma, Squamous Cell - drug therapy

Cell Line, Tumor

Inflammation - genetics

Head and Neck Neoplasms - genetics

Protein Kinase Inhibitors - pharmacology

Quinazolines - pharmacology

Details

Title: Subtitle: EGFR inhibition induces proinflammatory cytokines via NOX4 in HNSCC
Creators: Elise V M Fletcher - Department of Pathology, 1161 Medical Laboratories, University of Iowa, Iowa City, IA 52242. andrean-simons@uiowa.edu
Laurie Love-Homan
Arya Sobhakumari
Charlotte R Feddersen
Adam T Koch
Apollina Goel
Andrean L Simons
Resource Type: Journal article
Publication Details: Molecular cancer research, Vol.11(12), pp.1574-1584
DOI: 10.1158/1541-7786.MCR-13-0187
PMID: 24048704
PMCID: PMC3869882
NLM abbreviation: Mol Cancer Res
ISSN: 1541-7786
eISSN: 1557-3125
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS K01CA134941 / NCI NIH HHS T32 CA078586 / NCI NIH HHS R01 CA127958 / NCI NIH HHS R01CA127958 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS K01 CA134941 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 12/2013
Academic Unit: Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology
Record Identifier: 9984047862502771

Metrics

16 Record Views

45 Times Cited - Web of Science