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.
National Brain Research Centre, Manesar, Gurgaon, Haryana 122050, India.
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Dixit
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Sharma
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Ghosh
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Mehta
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Sen
D047310:Apigenin / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D004004:Dichlororibofuranosylbenzimidazole; D047310:Apigenin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D047390:Casein Kinase II; D019098:Telomerase; C447939:SIRT1 protein, human; D056564:Sirtuin 1