Abstract 4788: Protein kinase CK2 modulates TAp73 phosphorylation and suppresses apoptosis in head and neck cancer

The TP53 family member TAp73 has been shown to be pro-apoptotic and enhance chemosensitivity, but is inactivated in head and neck squamous cell carcinoma (HNSCC). We recently found that the inflammatory cytokine, TNFα, induces NF-κB activation and TAp73 nuclear export, which contribute to the suppression of TAp73 pro-apoptotic function. However, the intermediate signaling involved in TNFα regulated TAp73 inactivation and modulation of apoptosis has not been defined. Here, we found that TAp73 exhibits varying levels of phosphorylation in a panel of HNSCC cell lines. An inverse association between phospho- and total TAp73 protein expression was observed, suggesting that signal phosphorylation could contribute to TAp73 turnover. In response to TNFα treatment, phosphorylated TAp73 decreased in the nucleus while increasing in the cytoplasm, consistent with nuclear-cytoplasmic translocation. As we previously showed that protein kinase CK2 subunits are aberrantly overexpressed and promote IKK-NF-κB activation in HNSCC, we examined CK2 as a potential upstream regulator of TAp73 phosphorylation. Both CK2 inhibitor DMAT (2-Dimethy-lamino-4,5,6,7-tetrabromo-1H-benzimidazole) and CK2α siRNA inhibited TAp73 phosphorylation, as well as increased TAp73 mRNA and protein expression. Consequently, DMAT treatment increased the expression of TAp73 downstream pro-apoptotic genes, p21, PUMA and NOXA through increased TAp73 binding to the promoters of these genes. DMAT treatment and mutation of TAp73 phosphorylation sites increased p21 reporter activity. Furthermore, DMAT blocked cell cycle progression and proliferation, and increased apoptosis of HNSCC in vitro. Delivery of anti-CK2α/α′ oligodeoxy-nucleotide nanocapsules into HNSCC xenograft models significantly suppressed tumor growth, concomitant with decreased TAp73 phosphorylation, increased expression of TAp73, and target apoptotic proteins PUMA and NOXA. These results suggest that the aberrant activation of protein kinase CK2 could be one of the upstream signaling molecules modulating phosphorylation of TAp73, TAp73 nuclear exportation, and suppression of apoptosis in HNSCC cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4788. doi:10.1158/1538-7445.AM2011-4788