Protein kinase CK2 promotes cancer cell viability via up‐regulation of cyclooxygenase‐2 expression and enhanced prostaglandin E2 production

Abstract

Augmented expression of protein kinase CK2 is associated with hyperproliferation and resistance to apoptosis in cancer cells. Effects of CK2 are at least partially linked to signaling via the Wnt/β-catenin pathway, which is dramatically enhanced in colon cancer. Cyclooxygenase-2 (COX-2), a Wnt/β-catenin target gene, has been associated with enhanced cancer progression and metastasis. However, the possibility that a connection may exist between CK2 and COX-2 has not been explored previously. Here we investigated changes in COX-2 expression and activity upon CK2 modulation and evaluated how these changes affected cell viability. COX-2 expression and cell viability decreased upon selective inhibition of COX-2 with SC-791 or CK2 with 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT), both in human colon (HT29-ATCC, HT29-US, DLD-1) and breast (ZR-75) cancer cells, as well as in human embryonic kidney (HEK-293T) cells. On the other hand, ectopic CK2α expression promoted up-regulation of COX-2 by activating the Wnt/β-catenin pathway in HEK-293T cells. Noteworthy, over-expression of either CK2α, β-catenin or COX-2, as well as supplementation of the medium with prostaglandin E2 (PGE2), all were individually sufficient to overcome limitations in cell viability triggered by CK2 inhibition either upon addition of DMAT or over-expression of a dominant negative CK2α variant. Altogether, these findings provide new insight to the role of CK2 in cancer by up-regulating COX-2 expression and thereby PGE2 production.

Activation of protein kinase CK2 attenuates FOXO3a functioning in a PML-dependent manner: implications in human prostate cancer

“…29, 30 CK2 is abnormally deregulated in all human malignancies that have been examined till date, especially prostate cancer (PCa), 31 where CK2 plays an essential role in maintaining oncogenesis and related prognosis. The comprehensive effect of inhibition of CK2 on PC3 cells were established by inhibiting CK2 and observing the effects on cellular morphology (Figure 1a).…”

The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis

“…A recent study suggests that CK1ε is overexpressed in breast tumors and acts as a pivotal regulator of mRNA translation and cell proliferation. CK1ε phosphorylates the negative-acting factor 4E-BP1 (eukaryotic translation initiation factor 4E binding protein 1), thereby preventing its inhibitory function on the translation initiation complex elF4E (eukaryotic initiation factor 4E) and consequently leading to dysregulated mRNA translation and breast cancer cell growth (342). Elevated protein levels of CK1δ and ε were also observed in single tumor cells of grade 3 tumors of ductal pancreatic carcinomas and inhibition of CK1δ and ε by the CK1-specific inhibitor IC261 reduced pancreatic tumor cell growth in xenografts (339).…”

Transactivation activity and nucleocytoplasmic transport of β-catenin are independently regulated by its C-terminal end

“…CK2 enzyme is a Ser/Thr-kinase that phosphorylates over 300 proteins participating in many processes, such as replication, transcription, translation and signal transduction (Ahmed et al, 2002;Litchfield, 2003;Meggio and Pinna, 2003). CK2 participates as an important component of the canonical Wnt pathway by interacting and phosphorylating -catenin at residue Thr393 (Gao and Wang, 2006;Seldin et al, 2005;Song et al, 2003), thereby promoting expression of key proteins involved in tumor progression, such as survivin, cyclin D and COX-2 (Tapia et al, 2006;Ponce et al, 2011;Yefi et al, 2011), between many others. Furthermore, phosphorylation by CK2 has been implicated in regulation of bi-directional movement between nucleus and cytoplasm for diverse proteins.…”