title: Casein kinase 2 (CK2) increases survivin expression via enhanced beta-catenin-T cell factor/lymphoid enhancer binding factor-dependent transcription.
abstract: Increased expression of casein kinase 2 (CK2) is associated with hyperproliferation and suppression of apoptosis in cancer. Mutations in the tumor suppressor APC (adenomatous polyposis coli) are frequent in colon cancer and often augment beta-catenin-T cell factor (Tcf)/lymphoid enhancer binding factor (Lef)-dependent transcription of genes such as c-myc and cyclin-D1. CK2 has also been implicated recently in the regulation of beta-catenin stability. To identify mechanisms by which CK2 promotes survival, effects of the specific CK2 inhibitors 4,5,6,7-tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole were assessed. TBB and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole significantly decreased proliferation and increased apoptosis of HT29(US) colon cancer cells. RT-PCR and immunoblot analysis revealed that both inhibitors decreased survivin mRNA and protein levels in HT29(US) cells. Similar effects were observed with TBB in human DLD-1 and SW-480 colorectal cells as well as ZR-75 breast cancer cells and HEK-293T embryonic kidney cells. Expression of GFP-CK2alpha in HEK-293T cells resulted in beta-catenin-Tcf/Lef-dependent up-regulation of survivin and increased resistance to anticancer drugs. Augmented beta-catenin-Tcf/Lef-dependent transcription and resistance to apoptosis observed upon GFP-CK2alpha expression were abolished by TBB. Alternatively, HEK-293T cells expressing GFP-survivin were resistant to TBB-induced apoptosis. Finally, siRNA-mediated down-regulation of CK2alpha in HEK-293T cells coincided with reduced beta-catenin and survivin levels. Taken together, these results suggest that CK2 kinase activity promotes survival by increasing survivin expression via beta-catenin-Tcf/Lef-mediated transcription. Hence, selective CK2 inhibition or down-regulation in tumors may provide an attractive opportunity for the development of novel cancer therapies.
authors.affiliation: Laboratory of Cellular Communication, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 838-0453, Chile.
authors.forename: J C
authors.initials: JC
authors.lastname: Tapia
authors.forename: V A
authors.initials: VA
authors.lastname: Torres
authors.forename: D A
authors.initials: DA
authors.lastname: Rodriguez
authors.forename: L
authors.initials: L
authors.lastname: Leyton
authors.forename: A F G
authors.initials: AF
authors.lastname: Quest
mesh_terms: D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D000077022:Survivin; D051820:TCF Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000502:physiology*
chemical_list: C405354:4,5,6,7-tetrabromobenzotriazole; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D051820:TCF Transcription Factors; D014230:Triazoles; D051176:beta Catenin; D047390:Casein Kinase II