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 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.
Mesh Terms:
Apigenin, Apoptosis, Brain, Brain Neoplasms, Casein Kinase II, Cell Cycle Checkpoints, Cell Line, Tumor, Dichlororibofuranosylbenzimidazole, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, NF-kappa B, Protein Binding, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Signal Transduction, Sirtuin 1, Telomerase, Transfection, Tumor Necrosis Factor-alpha, Tumor Suppressor Protein p53
Apigenin, Apoptosis, Brain, Brain Neoplasms, Casein Kinase II, Cell Cycle Checkpoints, Cell Line, Tumor, Dichlororibofuranosylbenzimidazole, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, NF-kappa B, Protein Binding, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Signal Transduction, Sirtuin 1, Telomerase, Transfection, Tumor Necrosis Factor-alpha, Tumor Suppressor Protein p53
Cell Death Dis
Date: Feb. 10, 2012
PubMed ID: 22318540
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