Inhibition of Casein kinase-2 induces p53-dependent cell cycle arrest and sensitizes glioblastoma cells to tumor necrosis factor (TNFα)-induced apoptosis through SIRT1 inhibition

Glioblastoma multiforme (GBM) are resistant to TNF alpha-induced apoptosis and blockade of TNF alpha-induced NF-kappa B activation sensitizes glioma cells to apoptosis. As Casein kinase-2 (CK2) induces aberrant NF-kappa B activation and as we observed elevated CK2 levels in GBM tumors, we investigated the potential of CK2 inhibitors (CK2-Is) -DRB and Apigenin in sensitizing glioma cells to TNF alpha-induced apoptosis. CK2-Is and CK2 small interfering RNA (siRNA) reduced glioma cell viability, inhibited TNF alpha-mediated NF-kappa B activation, and sensitized cell to TNF alpha-induced apoptosis. Importantly, CK2-Is activated p53 function in wild-type but not in p53 mutant cells. Activation of p53 function involved its increased transcriptional activation, DNA-binding ability, increased expression of p53 target genes associated with cell cycle progression and apoptosis. Moreover, CK2-Is decreased telomerase activity and increased senescence in a p53-dependent manner. Apoptotic gene profiling indicated that CK2-Is differentially affect p53 and TNF alpha targets in p53 wild-type and mutant glioma cells. CK2-I decreased MDM2-p53 association and p53 ubiquitination to enhance p53 levels. Interestingly, CK2-Is downregulated SIRT1 activity and over-expression of SIRT1 decreased p53 transcriptional activity and rescued cells from CK2-I-induced apoptosis. This ability of CK2-Is to sensitize glioma to TNF alpha-induced death via multiple mechanisms involving abrogation of NF-kappa B activation, reactivation of wild-type p53 function and SIRT1 inhibition warrants investigation. Cell Death and Disease (2012) 3, e271; doi: 10.1038/cddis.2012.10; published online 9 February 2012