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Research Articles: Therapeutics, Targets, and Development

Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-B and activator protein-1 related mechanisms

¹ Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland and ² Department of Otolaryngology-Head and Neck Surgery, University of Minnesota Hospitals, Minneapolis, Minnesota

Requests for reprints: Carter Van Waes, Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, 10/5D55, MSC-1419, Bethesda, MD 20892-1419. Phone: 301-402-4216; Fax: 301-402-1140. E-mail: vanwaesc{at}nidcd.nih.gov

Abstract

Head and neck squamous cell carcinomas (HNSCC) exhibit constitutive activation of transcription factors nuclear factor-B (NF-B) and activator protein-1 (AP-1), which are modulated by the proteasome and promote resistance to cell death. HNSCC show variable sensitivity to the proteasome inhibitor bortezomib in vitro as well as in murine xenografts and patient tumors in vivo, and the mechanisms are not well understood. To address this question, the sensitivities of nine HNSCC cell lines to bortezomib were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and the potential relationship between the sensitivity and bortezomib effects on biological processes was examined in HNSCC lines of differential bortezomib sensitivity. The most sensitive cell line (UM-SCC-11B) underwent cell death at 10^–9 mol/L in vitro and tumor regression at a maximally tolerated dose of bortezomib in a murine xenograft model. The differential sensitivity between UM-SCC-11A and UM-SCC-11B cells corresponded to differences in the extent of suppression of proteasome activity, ubiquitinated protein degradation, and NF-B and AP-1 activation. Lower concentrations of bortezomib transiently increased NF-B and sustained AP-1 activation in UM-SCC-11A cells. AP-1 reporter activity and cell density of UM-SCC-11A were suppressed when bortezomib was combined with c-Jun NH₂-terminal kinase and p38 kinase pathways inhibitors. Thus, the differential sensitivities to bortezomib corresponded to dissimilar effects on the proteasome, NF-B and AP-1 activities. Inhibition of c-Jun NH₂-terminal kinase and p38 pathways blocked AP-1 activity and enhanced the antitumor effects. These findings revealed molecular mechanisms of bortezomib sensitivity and resistance, which are under development as biomarkers for clinical trials in patients with HNSCC. [Mol Cancer Ther 2008;7(7):1949–60]

Grant support: National Institute on Deafness and Other Communication Disorders intramural project Z01-DC-00016.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Bortezomib was provided for research under a Materials Cooperative Research and Development Agreement with Millennium Pharmaceuticals.

³ C. Van Waes, unpublished data.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁵ Z. Chen, unpublished observation.

Received 9/11/07; revised 3/25/08; accepted 4/ 1/08.