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      Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management

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          Abstract

          The Protein kinase CK2 (formerly known as casein kinase 2) is a highly conserved serine/ threonine kinase overexpressed in various human carcinomas and its high expression often correlates with poor prognosis. CK2 protein is localized in the nucleus of many tumor cells and correlates with clinical features in many cases. Increased expression of CK2 in mice results in the development of various types of carcinomas (both solids and blood related tumors, such as (breast carcinoma, lymphoma, etc), which reveals its carcinogenic properties. CK2 plays essential roles in many key biological processes related to carcinoma, including cell apoptosis, DNA damage responses and cell cycle regulation. CK2 has become a potential anti-carcinoma target. Various CK2 inhibitors have been developed with anti-neoplastic properties against a variety of carcinomas. Some CK2 inhibitors have showed good results in in vitro and pre-clinical models, and have even entered in clinical trials. This article will review effects of CK2 and its inhibitors on common carcinomas in in vitro and pre-clinical studies.

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          Protein kinase CK2: structure, regulation and role in cellular decisions of life and death.

          David W. Litchfield (2003)
          Protein kinase CK2 ('casein kinase II') has traditionally been classified as a messenger-independent protein serine/threonine kinase that is typically found in tetrameric complexes consisting of two catalytic (alpha and/or alpha') subunits and two regulatory beta subunits. Accumulated biochemical and genetic evidence indicates that CK2 has a vast array of candidate physiological targets and participates in a complex series of cellular functions, including the maintenance of cell viability. This review summarizes current knowledge of the structural and enzymic features of CK2, and discusses advances that challenge traditional views of this enzyme. For example, the recent demonstrations that individual CK2 subunits exist outside tetrameric complexes and that CK2 displays dual-specificity kinase activity raises new prospects for the precise elucidation of its regulation and cellular functions. This review also discusses a number of the mechanisms that contribute to the regulation of CK2 in cells, and will highlight emerging insights into the role of CK2 in cellular decisions of life and death. In this latter respect, recent evidence suggests that CK2 can exert an anti-apoptotic role by protecting regulatory proteins from caspase-mediated degradation. The mechanistic basis of the observation that CK2 is essential for viability may reside in part in this ability to protect cellular proteins from caspase action. Furthermore, this anti-apoptotic function of CK2 may contribute to its ability to participate in transformation and tumorigenesis.
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            One-thousand-and-one substrates of protein kinase CK2?

            Flavio Meggio, Lorenzo Pinna, Frank Rozsa (2003)
            CK2 (formerly termed "casein kinase 2") is a ubiquitous, highly pleiotropic and constitutively active Ser/Thr protein kinase whose implication in neoplasia, cell survival, and virus infection is supported by an increasing number of arguments. Here an updated inventory of 307 CK2 protein substrates is presented. More than one-third of these are implicated in gene expression and protein synthesis as being either transcriptional factors (60) or effectors of DNA/RNA structure (50) or translational elements. Also numerous are signaling proteins and proteins of viral origin or essential to virus life cycle. In comparison, only a minority of CK2 targets (a dozen or so) are classical metabolic enzymes. An analysis of 308 sites phosphorylated by CK2 highlights the paramount relevance of negatively charged side chains that are (by far) predominant over any other residues at positions n+3 (the most crucial one), n+1, and n+2. Based on this signature, it is predictable that proteins phosphorylated by CK2 are much more numerous than those identified to date, and it is possible that CK2 alone contributes to the generation of the eukaryotic phosphoproteome more so than any other individual protein kinase. The possibility that CK2 phosphosites play some global role, e.g., by destabilizing alpha helices, counteracting caspase cleavage, and generating adhesive motifs, will be discussed.
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              CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy.

              Adam Siddiqui-Jain, Denis Drygin, Nicole Streiner … (2010)
              Malignant transformation and maintenance of the malignant phenotype depends on oncogenic and non-oncogenic proteins that are essential to mediate oncogene signaling and to support the altered physiologic demands induced by transformation. Protein kinase CK2 supports key prosurvival signaling pathways and represents a prototypical non-oncogene. In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. The antiproliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2α catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. In models of angiogenesis, CX-4945 inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1α) transcription in cancer cells. When administered orally in murine xenograft models, CX-4945 was well tolerated and demonstrated robust antitumor activity with concomitant reductions of the mechanism-based biomarker phospho-p21 (T145). The observed antiproliferative and anti-angiogenic responses to CX-4945 in tumor cells and endothelial cells collectively illustrate that this compound exerts its antitumor effects through inhibition of CK2-dependent signaling in multiple pathways. Finally, CX-4945 is the first orally bioavailable small molecule inhibitor of CK2 to advance into human clinical trials, thereby paving the way for an entirely new class of targeted treatment for cancer. ©2010 AACR.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Asian Pac J Cancer Prev
                Journal ID (iso-abbrev): Asian Pac. J. Cancer Prev
                Title: Asian Pacific Journal of Cancer Prevention : APJCP
                Publisher: West Asia Organization for Cancer Prevention (Iran )
                ISSN (Print): 1513-7368
                ISSN (Electronic): 2476-762X
                Publication date (Print): 2019
                Volume: 20
                Issue: 1
                Pages: 23-32
                Affiliations
                [1 ]Department of Human Anatomy , School of Basic Medical Sciences, Wuhan, Hubei, P.R
                [2 ]Department of Gynaecology, Renmin Hospital, Wuhan University, Wuhan, Hubei, P.R
                [3 ]Shenzhen Institute of Wuhan University, Shenzhen, China
                Author notes
                [* ] For Correspondence: hueyfu@ 123456hotmail.com
                Article
                Publisher ID: APJCP-20-23
                DOI: 10.31557/APJCP.2019.20.1.23
                PMC ID: 6485562
                PubMed ID: 30677865
                SO-VID: a9c15649-8807-47ee-a683-602c0767d94a
                Copyright © Copyright: © Asian Pacific Journal of Cancer Prevention
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

                History
                Date received : 23 May 2018
                Date accepted : 06 December 2018
                Categories
                Subject: Review

                Keywords: protein kinase ck2,solid tumors,hematological tumors,cx-4945,cibg-300
                Data availability:
                Keywords: protein kinase ck2, solid tumors, hematological tumors, cx-4945, cibg-300

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