Casein kinase 2 (CK2) increases survivin expression via enhanced β-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 ␤-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 ␤-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-CK2␣ in HEK-293T cells resulted in ␤-catenin-Tcf͞Lef-dependent up-regulation of survivin and increased resistance to anticancer drugs. Augmented ␤-catenin-Tcf͞Lef-dependent transcription and resistance to apoptosis observed upon GFP-CK2␣ expression were abolished by TBB. Alternatively, HEK-293T cells expressing GFP-survivin were resistant to TBB-induced apoptosis. Finally, siRNA-mediated down-regulation of CK2␣ in HEK-293T cells coincided with reduced ␤-catenin and survivin levels. Taken together, these results suggest that CK2 kinase activity promotes survival by increasing survivin expression via ␤-catenin-Tcf͞Lef-mediated transcription. Hence, selective CK2 inhibition or down-regulation in tumors may provide an attractive opportunity for the development of novel cancer therapies.apoptosis ͉ cancer ͉ cell cycle

Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance phenotype of a CEM cell line characterized by high CK2 level

“…This is further supported by the results of Figure 9, where S-U2OS cells overexpressing a roughly double amount of CK2a survive significantly more than control cells to drug-induced apoptosis. In this respect, our data are consistent with already published works; very recently, Tapia et al (2006) and Ahmad et al (2007), for example reported on the protective effect from cytotoxic drugs of CK2a ectopically expressed in HEK-293T and prostatic cancer cells, respectively. Interestingly, Guo et al (2001) showed that the overexpression of a alone protects cells from chemical apoptosis similarly or even better than the expression of a and b together.…”

Protein kinase CK2 – A key suppressor of apoptosis

“…Among these, survivin has been shown to be influenced by the CK2 status in cells (Tapia et al, 2006). In accord with these observations, ongoing work in our laboratory has also shown that survivin expression cIAPs expression is reduced in prostate cancer cells upon downregulation of CK2; further, we have observed that cIAP1, cIAP2, and xIAP are also engaged downstream of the CK2 signal (Ahmed et al, unpublished data).…”

Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR‐32 neuroblastoma cells

“…The holoenzyme is a tetramer combination of either α 2 β 2 , α 2 β 2 , or αα β 2 . CK2 phosphorylates more than 300 proteins that participate in a broad range of cellular processes including replication, gene transcription, protein translation, signal transduction, cell death, and carcinogenesis [29]. Several lines of evidence provided in this study suggest CK2 as a major kinase for the phosphorylation of Nrf2 in the cells.…”