Abstract
In this study, we investigated the mechanisms underlying cetuximab-mediated radiosensitization of HNSCC. Irradiation of HNSCC cells upregulated hypoxia-inducible factor-1 alpha (HIF-1α) via a mechanism involving de novo synthesis of HIF-1α protein. Radiation-induced upregulation of HIF-1α was completely abolished by concurrent treatment of HNSCC cells with cetuximab. Experimental elevation of constitutively expressed HIF-1α abolished cetuximab-mediated radiosensitization in HNSCC cells, whereas downregulation of HIF-1α by siRNA or a small molecule inhibitor enhanced responses of cetuximab-resistant HNSCC cells to cetuximab plus radiation. Our data suggest that cetuximab sensitizes cancer cells to ionizing radiation in part through inhibition of radiation-induced upregulation of HIF-1α.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology*
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Carcinoma, Squamous Cell / radiotherapy*
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Cell Line, Tumor
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Cetuximab
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ErbB Receptors / antagonists & inhibitors*
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Genes, ras
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Head and Neck Neoplasms / radiotherapy*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology
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RNA, Small Interfering / genetics
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Radiation Tolerance
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Radiation-Sensitizing Agents / pharmacology*
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Squamous Cell Carcinoma of Head and Neck
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Up-Regulation
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Small Interfering
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Radiation-Sensitizing Agents
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ErbB Receptors
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Cetuximab