PMID:22318540

Citation	Dixit, D, Sharma, V, Ghosh, S, Mehta, VS and Sen, E (2012) 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. Cell Death Dis 3:e271
Abstract	Glioblastoma multiforme (GBM) are resistant to TNFα-induced apoptosis and blockade of TNFα-induced NF-κB activation sensitizes glioma cells to apoptosis. As Casein kinase-2 (CK2) induces aberrant NF-κB 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 TNFα-induced apoptosis. CK2-Is and CK2 small interfering RNA (siRNA) reduced glioma cell viability, inhibited TNFα-mediated NF-κB activation, and sensitized cell to TNFα-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 TNFα 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 TNFα-induced death via multiple mechanisms involving abrogation of NF-κB activation, reactivation of wild-type p53 function and SIRT1 inhibition warrants investigation.
Links	PubMed PMC3288342 Online version:10.1038/cddis.2012.10
Keywords	Apigenin/pharmacology; Apigenin/therapeutic use; Apoptosis; Brain/drug effects; Brain/metabolism; Brain/pathology; Brain Neoplasms/genetics; Brain Neoplasms/metabolism; Brain Neoplasms/pathology; Casein Kinase II/antagonists & inhibitors; Casein Kinase II/genetics; Cell Cycle Checkpoints/drug effects; Cell Line, Tumor; Dichlororibofuranosylbenzimidazole/pharmacology; Dichlororibofuranosylbenzimidazole/therapeutic use; Gene Expression Regulation, Neoplastic; Glioblastoma/genetics; Glioblastoma/metabolism; Glioblastoma/pathology; Humans; NF-kappa B/genetics; NF-kappa B/metabolism; Protein Binding/genetics; Protein Kinase Inhibitors/pharmacology; Proto-Oncogene Proteins c-mdm2/genetics; Proto-Oncogene Proteins c-mdm2/metabolism; RNA, Small Interfering/genetics; Signal Transduction; Sirtuin 1/antagonists & inhibitors; Sirtuin 1/genetics; Telomerase/genetics; Telomerase/metabolism; Transfection; Tumor Necrosis Factor-alpha/pharmacology; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/metabolism
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