Characterizing the convergence of protein kinase CK2 and caspase-3 reveals isoform-specific phosphorylation of caspase-3 by CK2α′: implications for pathological roles of CK2 in promoting cancer cell survival

Abstract

Protein kinase CK2 has emerged as a promising candidate for the treatment of a number of cancers. This enzyme is comprised of two catalytic subunits (CK2 and/or CK2α′) that form complexes with homodimers of regulatory CK2β subunits. While catalytic and regulatory CK2 subunits are generally expressed at similar levels to form tetrameric complexes, asymmetric expression of CK2 subunits has been associated with various forms of cancer and the enhanced survival of cancer cells. To elucidate mechanisms responsible for regulation of cancer cell survival by CK2, we recently employed computational and experimental strategies that revealed widespread overlap between sites for CK2 phosphorylation and caspase cleavage. Among candidates with overlapping CK2 and caspase cleavage sites was caspase-3 that is phosphorylated by CK2 to prevent its activation by upstream caspases. To elucidate the precise relationship between CK2 and caspase-3, we modulated expression of individual CK2 subunits and demonstrated that CK2α′ exhibits a striking preference for caspase-3 phosphorylation in cells as compared to CK2α and that CK2β exhibits the capacity to abolish caspase-3 phosphorylation. Since caspase-3 represents the first CK2 substrate selectively phosphorylated by CK2α′ in cells, our work highlights divergent functions of the different forms of CK2. Given the involvement of CK2 in a diverse series of biological events and its association with various cancers, this work has important implications for identifying pathological roles of distinct forms of CK2 that could instruct efforts to selectively target individual CK2 subunits for therapy.

Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

“…In this respect, CASP3 appears to be preferentially phosphorylated by CSNK2A2 rather than CSNK2A1, despite the fact that these two isoforms of CSNK2 have very similar enzymatic characteristics (16). Furthermore, CSNK2B attenuated phosphorylation, suggesting that misregulation of CSNK2 subunits in cells could be an additional mechanism to affect the regulation of apoptosis (12). The capacity of CSNK2 to promote cancer cell survival in vitro was also revealed in a recent large-scale screen via RNA interference knockdown and cDNA overexpression of kinases in DLD-1 colorectal adenocarcinoma cells in which overexpression of CSNK2A1 promoted resistance to TNFSF10 as determined by flow cytometry using antibodies against cleaved PARP and cleaved CASP3 (17).…”

“…2A) show that caspase substrates, including Bid, which promotes apoptotic progression when it is cleaved, can be phosphorylated by CSNK2 at sites adjacent to caspase cleavage sites. Because phosphorylation adjacent to caspase cleavage sites blocks cleavage, these observations suggest that increased phosphorylation by CSNK2 could promote cell survival by inhibiting caspase action (9)(10)(11)(12)(13)(14).…”

“…Going forward, applications of proteomic strategies to interrogate responses to CSNK2 inhibitors are expected to reveal signatures for CSNK2 inhibition and molecular insights to guide new strategies to interfere with its potential to inhibit caspase action or enhance the susceptibility of cancer cells to DNA damage. Clin Cancer Res; 22 (12); 2840-7. Ó2016 AACR.…”

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

“…CK2 is frequently overexpressed or overactive in aggressive forms of solid and hematological malignancies (2,3), and contributes to the dysregulation of cell growth, invasion, survival and senescence via the β-catenin, JAK/STAT, mTOR, and NF-κB pathways (4)(5)(6)(7)(8)(9). As a result, CK2 inhibitors have recently entered preliminary clinical trials for advanced solid and hematological tumors (source: ClinicalTrial.gov, accessed in December 2015).…”

“…CK2 has been reported to regulate tumor-initiating cell growth, tumor cell survival, DNA repair following ionizing radiation, and apoptosis in these tumors (4,5,7,8,(11)(12)(13). As a result, CK2 inhibition with drug inhibitors or siRNA technology was shown to alter the growth, survival and migration of glioma cell lines and slow down the growth of GBMs xenografts in immunodeficient mice (9,14).…”