Influence of Casein Kinase II in Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Rhabdomyosarcoma Cells
| Autor: | Janet A. Houghton, Leslie Douglas, Addison Delaney, Kamel Izeradjene |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
Programmed cell death Fas-Associated Death Domain Protein Green Fluorescent Proteins Mutation Missense Apoptosis X-Linked Inhibitor of Apoptosis Protein Biology Transfection Inhibitor of apoptosis Receptors Tumor Necrosis Factor TNF-Related Apoptosis-Inducing Ligand Small hairpin RNA Cell Line Tumor Rhabdomyosarcoma Humans Phosphorylation RNA Small Interfering Kinase activity Casein Kinase II Adaptor Proteins Signal Transducing Death domain Inhibitor of apoptosis domain Caspase 8 Membrane Glycoproteins Caspase 6 Tumor Necrosis Factor-alpha Proteins Mitochondria XIAP Isoenzymes Protein Subunits Receptors TNF-Related Apoptosis-Inducing Ligand Proto-Oncogene Proteins c-bcl-2 Oncology Drug Resistance Neoplasm Caspases Cancer research Benzimidazoles Casein kinase 2 Apoptosis Regulatory Proteins Signal Transduction |
| Zdroj: | Clinical Cancer Research. 10:6650-6660 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-04-0576 |
| Popis: | Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via the death receptors DR4 and DR5 in transformed cells in vitro and exhibits potent antitumor activity in vivo with minor side effects. Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli and is aberrantly elevated in a variety of human cancers. Rhabdomyosarcoma tumors are the most common soft-tissue sarcoma in childhood. In this investigation, we demonstrate that CK2 is a key survival factor that protects tumor cells from TRAIL-induced apoptosis. We have demonstrated that inhibition of CK2 phosphorylation events by 5,6-dichlorobenzimidazole (DRB) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis. CK2 inhibition also induced rapid cleavage of caspase-8, -9, and -3, as well as the caspase substrate poly(ADP-ribose) polymerase after TRAIL treatment. Overexpression of Bcl-2 protected cells from TRAIL-induced apoptosis in the presence of the CK2 inhibitor. Death signaling by TRAIL in these cells was Fas-associated death domain and caspase dependent because dominant negative Fas-associated death domain or the cowpox interleukin 1β-converting enzyme inhibitor protein cytokine response modifier A prevented apoptosis in the presence of DRB. Analysis of death-inducing signaling complex (DISC) formation demonstrated that inhibition of CK2 by DRB increased the level of recruitment of procaspase-8 to the DISC and enhanced caspase-8-mediated cleavage of Bid, thereby increasing the release of the proapoptotic factors cytochrome c, HtrA2/Omi, Smac/DIABLO, and apoptosis inducing factor (AIF) from the mitochondria, with subsequent degradation of X-linked inhibitor of apoptosis protein (XIAP). To further interfere with CK2 function, JR1 and Rh30 cells were transfected with either short hairpin RNA targeted to CK2α or kinase-inactive CK2α (K68M) or CK2α′ (K69M). Data show that the CK2 kinase activity was abrogated and that TRAIL sensitivity in both cell lines was increased. Silencing of CK2α expression with short hairpin RNA was also associated with degradation of XIAP. These findings suggest that CK2 regulates TRAIL signaling in rhabdomyosarcoma by modulating TRAIL-induced DISC formation and XIAP expression. |
| Databáze: | OpenAIRE |
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