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Protein Kinase Casein Kinase 2 Mediates Inhibitor-B Kinase and Aberrant Nuclear Factor-B Activation by Serum Factor(s) in Head and Neck Squamous Carcinoma Cells

Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland

Requests for reprints: Carter Van Waes, Head and Neck Surgery Branch, Building 10, CRC Room 4-2732, 10 Center Drive, Bethesda, MD 20892. Phone: 301-402-2001; Fax: 301-402-1140; E-mail: vanwaesc{at}nidcd.nih.gov.

We showed previously that the signal transcription factor nuclear factor-B (NF-B) is aberrantly activated and that inhibition of NF-B induces cell death and inhibits tumorigenesis in head and neck squamous cell carcinomas (HNSCC). Thus, identification of specific kinases underlying the activation of NF-B could provide targets for selective therapy. Inhibitor-B (IB) kinase (IKK) is known to activate NF-B by inducing NH₂-terminal phosphorylation and degradation of its endogenous inhibitor, IB. Casein kinase 2 (CK2) was previously reported to be overexpressed in HNSCC cells and to be a COOH-terminal IKK, but its relationship to NF-B activation in HNSCC cells is unknown. In this study, we examined the contribution of IKK and CK2 in the regulation of NF-B in HNSCC in vitro. NF-B activation was specifically inhibited by kinase-dead mutants of the IKK1 and IKK2 subunits or small interfering RNA targeting the ß subunit of CK2. CK2 and IKK kinase activity, as well as NF-B transcriptional activity, was shown to be serum responsive, indicating that these kinases mediate aberrant activation of NF-B in response to serum factor(s) in vitro. Recombinant CK2 was shown to phosphorylate recombinant IKK2 as well as to promote immunoprecipitated IKK complex from HNSCC to phosphorylate the NH₂-terminal S32/S36 of IB. We conclude that the aberrant NF-B activity in HNSCC cells in response to serum is partially through a novel mechanism involving CK2-mediated activation of IKK2, making these kinases candidates for selective therapy to target the NF-B pathway in HNSCC. (Cancer Res 2006; 66(13): 6722-31)

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