CK2 Modulation of NF-κB, TP53, and the Malignant Phenotype in Head and Neck Cancer by Anti-CK2 OligonucleotidesIn vitroorIn vivovia Sub–50-nm Nanocapsules

Abstract

Purpose: The aim of this study is to investigate the expression of CK2 subunits and CK2 effects on NF-κB-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-κB 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 CK2α/α′ in HNSCC xenograft models was achieved using anti-CK2α/α′ 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 IκBα degradation, NF-κB nuclear localization, phosphorylation, DNA binding, and reporter activity. CK2 subunits modulated gene expression and the malignant phenotype involved in cell cycle and migration, whereas CK2α is critical to promote proliferation, antiapoptosis, and cisplatin resistance in vitro. Furthermore, in vivo delivery of anti-CK2α/α′ oligodeoxynucleotide nanocapsules significantly suppressed tumor growth in HNSCC xenograft models, in association with modulation of CK2 and NF-κB regulated molecules, TP53 family proteins, and induction of apoptosis.Conclusions: Our study reveals a novel role of CK2 in coregulating NF-κB 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.

LYG-202 Augments Tumor Necrosis Factor-α-Induced Apoptosis via Attenuating Casein Kinase 2-Dependent Nuclear Factor-κB Pathway in HepG2 Cells

“…These findings promote CK2 as an unfavorable prognostic marker in several cancers and consequently as a relevant therapeutic target (Prudent et al, 2010;Sun et al, 2010;Trembley et al, 2010). Recent studies report that CK2 contributes to aberrant NF-B activation though enhancement of IKK␤ activity for the phosphorylation of the Ser32/Ser36 NH 2 terminus of IB␣, a novel and distinct function from that of CK2 as a known COOH-terminal IKK␤ (Yu et al, 2006;Brown et al, 2010). Inverse docking indicated that CK2 may be a potent target of LYG-202 in blocking of NF-B activation.…”

“…We know that TNF-␣ triggers both the caspase-protease pathway and the NF-B pathway, and the balance of these two pathways is critical for the ultimate fate of a cell: death or survival (Brown et al, 2010). These findings prompted us to determine whether LYG-202 could enhance TNF-␣-induced apoptosis by attenuating the NF-B pathway.…”

CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination Therapy

“…Indeed, sensitization of pancreatic cancer cells to gemcitabine and head and neck cancer cells to cisplatin by genetic manipulation of CK2 expression has been attributed to resulting suppression of Akt and NF-kB activity, respectively (47,48). Thus it is possible that in addition to the suppression of DNA repair response, CX-4945 enhances activity of gemcitabine and cisplatin by modulating PI3K/Akt and NF-kB signaling.…”

Can non-viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics?

“…siRNA against CK2 subunits was encapsulated inside tenfibgen nanocapsules and administered by intratumoural injection into a HNSCC xenograft animal model, resulting in suppression of tumour size accompanied with modulation of CK2 and NF-kappaB regulated molecules and induction of apoptosis (Brown et al, 2010). Another Phase I clinical trial (Atu027) has been announced by Silence Therapeutics to treat a broad range of solid tumours including gastrointestinal (including pancreatic), non-small cell lung, prostate, melanoma, liver and others (www.silence-therapeutics.com).…”