Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, NF-κB and AP-1 related mechanisms

• Published in: Molecular cancer therapeutics 2008-07, Vol.7 (7), p.1949-1960
• Main Authors: Chen, Zhong, Ricker, Justin L., Malhotra, Pramit S., Nottingham, Liesl, Bagain, Lorena, Lee, Tin Lap, Yeh, Ning T, Van Waes, Carter
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-07-2046

Head and neck squamous cell carcinomas (HNSCC) exhibit constitutive activation of transcription factors NF-κB and 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 MTT assays, and the potential relationship between the sensitivity and bortezomib effects on biological processes were examined in HNSCC lines of differential bortezomib sensitivity. The most sensitive cell line (UM-SCC-11B) underwent cell death at 10 –9 M 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 -11B cells corresponded to differences in the extent of suppression of proteasome activity, ubiquitinated protein degradation, and NF-κB and AP-1 activation. Lower concentrations of bortezomib transiently increased NF-κB 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 JNK and p38 kinase pathways inhibitors. Thus, the differential sensitivities to bortezomib corresponded to dissimilar effects on the proteasome, NF-κB and AP-1 activities. Inhibition of JNK and p38 pathways blocked AP-1 activity and enhanced the anti-tumor effects. These findings revealed molecular mechanisms of bortezomib sensitivity and resistance which are under development as biomarkers for clinical trials in patients with HNSCC.