Abstract |
Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli, as well as being elevated in many human cancers examined. We have demonstrated that CK2 is a key survival factor that protects human colon carcinoma cells from TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. We determined that inhibition of CK2 phosphorylation events by DRB (5,6-dichlorobenzimidazole) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis, in the absence of effects in normal cells. Sensitization was caspase dependent, and independent of regulation via NF-kappaB. Further, inhibition of phosphorylation by CK2 did not modify the expression level of antiapoptotic proteins. Analysis of TRAIL-induced death-inducing signaling complex (DISC) formation demonstrated enhanced formation of the DISC, enhanced cleavage of caspase-8 and cleavage of Bid in the presence of DRB, thereby facilitating the release of proapoptotic factors from the mitochondria with subsequent downregulation of the expression of XIAP and c-IAP1. Further, silencing of CK2alpha in HT29 cells following transfection of CK2alpha shRNA abrogated CK2 kinase activity while simultaneously increasing TRAIL sensitivity. These findings demonstrate that CK2 plays a critical antiapoptotic role by conferring resistance to TRAIL at the level of the DISC.
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Authors | Kamel Izeradjene, Leslie Douglas, Addison Delaney, Janet A Houghton |
Journal | Oncogene
(Oncogene)
Vol. 24
Issue 12
Pg. 2050-8
(Mar 17 2005)
ISSN: 0950-9232 [Print] England |
PMID | 15688023
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Apoptosis Regulatory Proteins
- Death Domain Receptor Signaling Adaptor Proteins
- Enzyme Inhibitors
- Indoles
- Maleimides
- Membrane Glycoproteins
- Receptors, Tumor Necrosis Factor
- Recombinant Proteins
- TNF-Related Apoptosis-Inducing Ligand
- TNFSF10 protein, human
- Tumor Necrosis Factor-alpha
- Apigenin
- Casein Kinase II
- bisindolylmaleimide
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Topics |
- Adenocarcinoma
- Apigenin
(pharmacology)
- Apoptosis
(physiology)
- Apoptosis Regulatory Proteins
- Casein Kinase II
(metabolism)
- Cell Death
(drug effects, physiology)
- Cell Line, Tumor
- Colonic Neoplasms
- Death Domain Receptor Signaling Adaptor Proteins
- Enzyme Inhibitors
(pharmacology)
- Genetic Vectors
- Humans
- Indoles
(pharmacology)
- Kinetics
- Maleimides
(pharmacology)
- Membrane Glycoproteins
(metabolism)
- Receptors, Tumor Necrosis Factor
(physiology)
- Recombinant Proteins
(metabolism)
- TNF-Related Apoptosis-Inducing Ligand
- Transfection
- Tumor Necrosis Factor-alpha
(metabolism)
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