Molecular targeting CK2 by siRNA or antisense delivered by tenfibgen ligand nanocapsules modulates NF-kappaB, TP53 and the malignant phenotype in head and neck cancer

We previously reported that protein kinase CK2 contributes to aberrant NF‐kappaB activation, but the molecular mechanisms and antitumor effects of targeting CK2 have not been thoroughly investigated in head and neck squamous cell carcinoma (HNSCC). In the present study, we showed elevated CK2alpha, alpha9 and beta mRNA and protein expression in a panel of HNSCC lines and tissues. siRNA specifically knocked down CK2 subunits and differentially inhibited IKKbeta mediated IkappaBalpha degradation, p65 synthesis and phosphorylation at serine 536 and 529, p65 and p50 binding, and NF‐kappaB reporter activities. CK2alpha knockdown also upregulated two genes promoting apoptosis, TP53 and TAp63, which together with inhibition of NF‐kappaB downregulated genes promoting growth, survival and adhesion, such as CyclinD1, BCL‐XL, ITGA3, and ITGB4. Knockdown of CK2alpha9 or beta also exhibited differential effects on gene expression. Consequently, CK2alpha siRNA most significantly inhibited proliferation, cell cycle, and migration, while inducing apoptosis and cisplatin sensitivity in vitro. Furthermore, delivery of antisense targeting CK2alpha and alpha9 using tenfibgen (fibrinogen fragment of tenascin) coated nanocapsules significantly suppressed tumor growth in HNSCC xenograft models. Consistent with CK2 inhibition, antisense‐treated tumor tissue specimens showed decreased expression of CK2alpha and alpha9, NF‐kappaB p65, Cyclin D1, Bcl‐XL and Bcl2 proteins, decreased NF‐kappaB p65 phosphorylation at serine 536 and 529, as well as increased TP53 and p63 by immunohistochemistry. Our study revealed the novel role of CK2 subunits in co‐regulating NF‐kappaB and TP53/p63 expression and signaling, as well as downstream gene expression, which result in anti‐tumor effects in vitro and in vivo. Targeting the CK2 subunits may be an effective antitumor strategy with the ability to enhance the efficacy of cisplatin chemotherapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C156.