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B.
Address correspondence to Robert E. Brown, M.D., Division of Laboratory Medicine, Geisinger Medical Center, 100 North Academy Ave., Danville, PA 17822, USA; tel 570 274 9781; fax 570 271 6105; e-mail: rebrown{at}geisinger.edu.
Background: Nuclear factor-kappaB (NF-
B) is synthesized in the cytoplasm, complexed with its inhibitor, I-B, and NF-B is released in an activated (phosphorylated) form following phosphorylation of I-B and proteasomal degradation of the NF-B•p-B complex. The free p-NF-B can then be translocated to the nucleus where it effects transcriptional activation of genes leading to the synthesis of proteins that are generally pro-growth and anti-apoptosis. Objective: To gain insight into the role of the NF-B pathway in head and neck squamous cell carcinoma (HNSCC), we selected two HNSCC cell lines, SCC-15 of lingual origin and FaDu of pharyngeal origin, with constitutively activated (phosphorylated) NF-B. We assessed the impact of interrupting the NF-B pathway at the level of proteasomal degradation using Velcade (bortezomib), a proteasome inhibitor, and at the pretranslational level in the synthesis of NF-B using a small interfering RNA (siRNA). Results: Velcade produced a dose-dependent inhibition of cell growth in both cell lines. At 30 nM, Velcade inhibited cell growth in the SCC-15 cell line by 40%. In both cell lines, Velcade induced nuclear overexpression of p21WAF1, an inhibitor of G1 cell cycle progression, which appeared to be independent of p53 expression. Addition of siRNA augmented the inhibitory effects of Velcade in FaDu cells; siRNA/NF-B alone led to a 48% decline in basal expression of NF-B protein levels and effected a 25% inhibition of cell growth. In the presence of Velcade (30 nM), siRNA/NF-B increased growth inhibition from 43 to 65%. Conclusions: The mechanisms involved in growth inhibitory effects of Velcade on HNSCC cell lines include the NF-B pathway, suggesting the possible therapeutic use of Velcade or other NF-B pathway inhibitors (eg, curcumin). The data also suggest that combining siRNA/NF-B with Velcade might achieve greater reduction in the growth of HNSCC in patients with constitutively activated NF-B.
Keywords: squamous cell carcinoma, NF-B, Velcade, siRNA
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