CK2 Modulation of NF-κB, TP53, and the Malignant Phenotype in Head and Neck Cancer by Anti-CK2 Oligonucleotides In vitro or In vivo via Sub-50-nm Nanocapsules

Purpose: The aim of this study is to investigate the expression of CK2 subunits and CK2 effects on NF kappa B-mediated and TP53-mediated signal activation and gene expression, the malignant phenotype, and chemosensitivity in head and neck squamous cell carcinoma (HNSCC) in vitro and in vivo. Experimental Design: Protein expression of CK2 subunits was investigated by Western blot and immunohistochemistry. CK2 subunits were knocked down by small interfering RNA, and NF-kappa B activation was examined using DNA binding, Western blot, and luciferase reporter assays. Gene expression was measured by quantitative reverse transcription-PCR. Cell growth, survival, motility, and sensitivity to cisplatin were measured by MTT, flow cytometry, and migration assays. In vivo targeting of CK2 alpha/alpha' in HNSCC xenograft models was achieved using anti-CK2 alpha/alpha' oligodeoxynucleotide encapsulated in sub-50-nm tenfibgen nanocapsules. Results: CK2 subunit proteins were overexpressed in HNSCC lines and tissues. Knockdown of CK2 subunits differentially inhibited I kappa B alpha degradation, NF-kappa B nuclear localization, phosphorylation, DNA binding, and reporter activity. CK2 subunits modulated gene expression and the malignant phenotype involved in cell cycle and migration, whereas CK2 alpha is critical to promote proliferation, antiapoptosis, and cisplatin resistance in vitro. Furthermore, in vivo delivery of anti-CK2 alpha/alpha' oligodeoxynucleotide nanocapsules significantly suppressed tumor growth in HNSCC xenograft models, in association with modulation of CK2 and NF-kappa B regulated molecules, TP53 family proteins, and induction of apoptosis. Conclusions: Our study reveals a novel role of CK2 in coregulating NF-kappa B activation, TP53/p63 expression, and downstream gene expression. Downregulation of CK2 in HNSCC models in vitro and in vivo shows antitumor effects as well as sensitization to cisplatin. Clin Cancer Res; 16(8); 2295-307. (C) 2010 AACR.