CK2 Regulation of Cell Death and Targeting in Cancer Treatment

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 26280

Special Issue Editors

1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
2. Research Service, Minneapolis VA Health Care System, Minneapolis, MN 55417, USA
Interests: protein kinase CK2 signal mechanisms; therapy targeting
Special Issues, Collections and Topics in MDPI journals
1. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
2. Research Service, Minneapolis VA Health Care System, Minneapolis, MN 55417, USA
Interests: protein kinase CK2; CDK11 signal mechanisms; therapy targeting
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein kinases are a significant portion of the genome with diverse roles. Of the large family of protein kinases, CK2 (previously casein kinase 2 or II) has emerged as a „master regulator“ of a wide range of cellular activities in normal as well as disease states. An aspect that has gained much attention is its nearly uniform dysregulation in all cancers studied. Originally, it was believed that the elevation of CK2 was a reflection of its involvement in cell growth and proliferation, as it was high in both normal proliferating cells and cancer cells. However, subsequently, it became clear that CK2 was a potent suppressor of cell death. With the knowledge that CK2 is essential for cell survival and its targeting results in cell death, CK2 emerged as an important target for cancer therapy. Given the significance of the evolving progress in this area of research, a special section of Biomedicines is dedicated to providing a venue for investigators to publish their research.

Prof. Dr. Khalil Ahmed
Guest Editor

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Keywords

  • CK2
  • casein kinase 2
  • apoptosis
  • cell death
  • proliferation
  • therapeutic targeting
  • oncology
  • cancer

Published Papers (8 papers)

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Research

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16 pages, 5359 KiB  
Article
CIGB-300 Anticancer Peptide Differentially Interacts with CK2 Subunits and Regulates Specific Signaling Mediators in a Highly Sensitive Large Cell Lung Carcinoma Cell Model
by George V. Pérez, Mauro Rosales, Ailyn C. Ramón, Arielis Rodríguez-Ulloa, Vladimir Besada, Luis J. González, Daylen Aguilar, Dania Vázquez-Blomquist, Viviana Falcón, Evelin Caballero, Paulo C. Carvalho, Rodrigo Soares Caldeira, Ke Yang, Yasser Perera and Silvio E. Perea
Biomedicines 2023, 11(1), 43; https://doi.org/10.3390/biomedicines11010043 - 25 Dec 2022
Cited by 2 | Viewed by 1422
Abstract
Large cell lung carcinoma (LCLC) is one form of NSCLC that spreads more aggressively than some other forms, and it represents an unmet medical need. Here, we investigated for the first time the effect of the anti-CK2 CIGB-300 peptide in NCI-H460 cells as [...] Read more.
Large cell lung carcinoma (LCLC) is one form of NSCLC that spreads more aggressively than some other forms, and it represents an unmet medical need. Here, we investigated for the first time the effect of the anti-CK2 CIGB-300 peptide in NCI-H460 cells as an LCLC model. NCI-H460 cells were highly sensitive toward CIGB-300 cytotoxicity, reaching a peak of apoptosis at 6 h. Moreover, CIGB-300 slightly impaired the cell cycle of NCI-H460 cells. The CIGB-300 interactomics profile revealed in more than 300 proteins that many of them participated in biological processes relevant in cancer. Interrogation of the CK2 subunits targeting by CIGB-300 indicated the higher binding of the peptide to the CK2α′ catalytic subunit by in vivo pull-down assays plus immunoblotting analysis and confocal microscopy. The down-regulation of both phosphorylation and protein levels of the ribonuclear protein S6 (RPS6) was observed 48 h post treatment. Altogether, we have found that NCI-H460 cells are the most CIGB-300-sensitive solid tumor cell line described so far, and also, the findings we provide here uncover novel features linked to CK2 targeting by the CIGB-300 anticancer peptide. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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14 pages, 2210 KiB  
Article
Inhibition of CK2 Reduces NG2 Expression in Juvenile Angiofibroma
by Anne S. Boewe, Silke Wemmert, Philipp Kulas, Bernhard Schick, Claudia Götz, Selina Wrublewsky, Mathias Montenarh, Michael D. Menger, Matthias W. Laschke and Emmanuel Ampofo
Biomedicines 2022, 10(5), 966; https://doi.org/10.3390/biomedicines10050966 - 21 Apr 2022
Cited by 4 | Viewed by 1607
Abstract
Juvenile angiofibroma (JA) is a rare fibrovascular neoplasm predominately found within the posterior nasal cavity of adolescent males. JA expresses the proteoglycan nerve–glial antigen (NG)2, which crucially determines the migratory capacity of distinct cancer cells. Moreover, it is known that the protein kinase [...] Read more.
Juvenile angiofibroma (JA) is a rare fibrovascular neoplasm predominately found within the posterior nasal cavity of adolescent males. JA expresses the proteoglycan nerve–glial antigen (NG)2, which crucially determines the migratory capacity of distinct cancer cells. Moreover, it is known that the protein kinase CK2 regulates NG2 gene expression. Therefore, in the present study, we analyzed whether the inhibition of CK2 suppresses NG2-dependent JA cell proliferation and migration. For this purpose, we assessed the expression of NG2 and CK2 in patient-derived JA tissue samples, as well as in patient-derived JA cell cultures by Western blot, immunohistochemistry, flow cytometry and quantitative real-time PCR. The mitochondrial activity, proliferation and migratory capacity of the JA cells were determined by water-soluble tetrazolium (WST)-1, 5-bromo-2′-deoxyuridine (BrdU) and collagen sprouting assays. We found that NG2 and CK2 were expressed in both the JA tissue samples and cell cultures. The treatment of the JA cells with the two CK2 inhibitors, CX-4945 and SGC-CK2-1, significantly reduced NG2 gene and protein expression when compared to the vehicle-treated cells. In addition, the loss of CK2 activity suppressed the JA cell proliferation and migration. These findings indicate that the inhibition of CK2 may represent a promising therapeutic approach for the treatment of NG2-expressing JA. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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18 pages, 4180 KiB  
Article
Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
by Mauro Rosales, George V. Pérez, Ailyn C. Ramón, Yiliam Cruz, Arielis Rodríguez-Ulloa, Vladimir Besada, Yassel Ramos, Dania Vázquez-Blomquist, Evelin Caballero, Daylen Aguilar, Luis J. González, Katharina Zettl, Jacek R. Wiśniewski, Ke Yang, Yasser Perera and Silvio E. Perea
Biomedicines 2021, 9(7), 766; https://doi.org/10.3390/biomedicines9070766 - 01 Jul 2021
Cited by 11 | Viewed by 2886
Abstract
Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based [...] Read more.
Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), an advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML-targeted therapy. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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16 pages, 3452 KiB  
Article
CX-4945 and siRNA-Mediated Knockdown of CK2 Improves Cisplatin Response in HPV(+) and HPV(−) HNSCC Cell Lines
by Janeen H. Trembley, Bin Li, Betsy T. Kren, Amy A. Gravely, Emiro Caicedo-Granados, Mark A. Klein and Khalil Ahmed
Biomedicines 2021, 9(5), 571; https://doi.org/10.3390/biomedicines9050571 - 18 May 2021
Cited by 7 | Viewed by 2919
Abstract
Head and neck squamous cell carcinoma (HNSCC) can be categorized into human papillomavirus (HPV) positive or negative disease. Elevated protein kinase CK2 level and activity have been historically observed in HNSCC cells. Previous studies on CK2 in HNSCC did not generally include consideration [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) can be categorized into human papillomavirus (HPV) positive or negative disease. Elevated protein kinase CK2 level and activity have been historically observed in HNSCC cells. Previous studies on CK2 in HNSCC did not generally include consideration of HPV(+) and HPV(−) status. Here, we investigated the response of HPV(+) and HPV(−) HNSCC cells to CK2 targeting using CX-4945 or siRNA downregulation combined with cisplatin treatment. HNSCC cell lines were examined for CK2 expression levels and activity and response to CX-4945, with and without cisplatin. CK2 levels and NFκB p65-related activity were high in HPV(+) HNSCC cells relative to HPV(−) HNSCC cells. Treatment with CX-4945 decreased viability and cisplatin IC50 in all cell lines. Targeting of CK2 increased tumor suppressor protein levels for p21 and PDCD4 in most instances. Further study is needed to understand the role of CK2 in HPV(+) and HPV(−) HNSCC and to determine how incorporation of the CK2-targeted inhibitor CX-4945 could improve cisplatin response in HNSCC. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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Review

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18 pages, 1340 KiB  
Review
Protein Kinase CK2 and Epstein–Barr Virus
by Mathias Montenarh, Friedrich A. Grässer and Claudia Götz
Biomedicines 2023, 11(2), 358; https://doi.org/10.3390/biomedicines11020358 - 26 Jan 2023
Cited by 2 | Viewed by 1599
Abstract
Protein kinase CK2 is a pleiotropic protein kinase, which phosphorylates a number of cellular and viral proteins. Thereby, this kinase is implicated in the regulation of cellular signaling, controlling of cell proliferation, apoptosis, angiogenesis, immune response, migration and invasion. In general, viruses use [...] Read more.
Protein kinase CK2 is a pleiotropic protein kinase, which phosphorylates a number of cellular and viral proteins. Thereby, this kinase is implicated in the regulation of cellular signaling, controlling of cell proliferation, apoptosis, angiogenesis, immune response, migration and invasion. In general, viruses use host signaling mechanisms for the replication of their genome as well as for cell transformation leading to cancer. Therefore, it is not surprising that CK2 also plays a role in controlling viral infection and the generation of cancer cells. Epstein–Barr virus (EBV) lytically infects epithelial cells of the oropharynx and B cells. These latently infected B cells subsequently become resting memory B cells when passing the germinal center. Importantly, EBV is responsible for the generation of tumors such as Burkitt’s lymphoma. EBV was one of the first human viruses, which was connected to CK2 in the early nineties of the last century. The present review shows that protein kinase CK2 phosphorylates EBV encoded proteins as well as cellular proteins, which are implicated in the lytic and persistent infection and in EBV-induced neoplastic transformation. EBV-encoded and CK2-phosphorylated proteins together with CK2-phosphorylated cellular signaling proteins have the potential to provide efficient virus replication and cell transformation. Since there are powerful inhibitors known for CK2 kinase activity, CK2 might become an attractive target for the inhibition of EBV replication and cell transformation. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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63 pages, 3502 KiB  
Review
CK2 and the Hallmarks of Cancer
by May-Britt Firnau and Angela Brieger
Biomedicines 2022, 10(8), 1987; https://doi.org/10.3390/biomedicines10081987 - 16 Aug 2022
Cited by 11 | Viewed by 2996
Abstract
Cancer is a leading cause of death worldwide. Casein kinase 2 (CK2) is commonly dysregulated in cancer, impacting diverse molecular pathways. CK2 is a highly conserved serine/threonine kinase, constitutively active and ubiquitously expressed in eukaryotes. With over 500 known substrates and being estimated [...] Read more.
Cancer is a leading cause of death worldwide. Casein kinase 2 (CK2) is commonly dysregulated in cancer, impacting diverse molecular pathways. CK2 is a highly conserved serine/threonine kinase, constitutively active and ubiquitously expressed in eukaryotes. With over 500 known substrates and being estimated to be responsible for up to 10% of the human phosphoproteome, it is of significant importance. A broad spectrum of diverse types of cancer cells has been already shown to rely on disturbed CK2 levels for their survival. The hallmarks of cancer provide a rationale for understanding cancer’s common traits. They constitute the maintenance of proliferative signaling, evasion of growth suppressors, resisting cell death, enabling of replicative immortality, induction of angiogenesis, the activation of invasion and metastasis, as well as avoidance of immune destruction and dysregulation of cellular energetics. In this work, we have compiled evidence from the literature suggesting that CK2 modulates all hallmarks of cancer, thereby promoting oncogenesis and operating as a cancer driver by creating a cellular environment favorable to neoplasia. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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15 pages, 2004 KiB  
Review
The Immune Regulatory Role of Protein Kinase CK2 and Its Implications for Treatment of Cancer
by Huixian Hong and Etty N. Benveniste
Biomedicines 2021, 9(12), 1932; https://doi.org/10.3390/biomedicines9121932 - 17 Dec 2021
Cited by 12 | Viewed by 6662
Abstract
Protein Kinase CK2, a constitutively active serine/threonine kinase, fulfills its functions via phosphorylating hundreds of proteins in nearly all cells. It regulates a variety of cellular signaling pathways and contributes to cell survival, proliferation and inflammation. CK2 has been implicated in the pathogenesis [...] Read more.
Protein Kinase CK2, a constitutively active serine/threonine kinase, fulfills its functions via phosphorylating hundreds of proteins in nearly all cells. It regulates a variety of cellular signaling pathways and contributes to cell survival, proliferation and inflammation. CK2 has been implicated in the pathogenesis of hematologic and solid cancers. Recent data have documented that CK2 has unique functions in both innate and adaptive immune cells. In this article, we review aspects of CK2 biology, functions of the major innate and adaptive immune cells, and how CK2 regulates the function of immune cells. Finally, we provide perspectives on how CK2 effects in immune cells, particularly T-cells, may impact the treatment of cancers via targeting CK2. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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18 pages, 1823 KiB  
Review
CK2 Regulation: Perspectives in 2021
by Scott E. Roffey and David W. Litchfield
Biomedicines 2021, 9(10), 1361; https://doi.org/10.3390/biomedicines9101361 - 30 Sep 2021
Cited by 34 | Viewed by 4279
Abstract
The protein kinase CK2 (CK2) family encompasses a small number of acidophilic serine/threonine kinases that phosphorylate substrates involved in numerous biological processes including apoptosis, cell proliferation, and the DNA damage response. CK2 has also been implicated in many human malignancies and other disorders [...] Read more.
The protein kinase CK2 (CK2) family encompasses a small number of acidophilic serine/threonine kinases that phosphorylate substrates involved in numerous biological processes including apoptosis, cell proliferation, and the DNA damage response. CK2 has also been implicated in many human malignancies and other disorders including Alzheimer′s and Parkinson’s diseases, and COVID-19. Interestingly, no single mechanism describes how CK2 is regulated, including activation by external proteins or domains, phosphorylation, or dimerization. Furthermore, the kinase has an elongated activation loop that locks the kinase into an active conformation, leading CK2 to be labelled a constitutively active kinase. This presents an interesting paradox that remains unanswered: how can a constitutively active kinase regulate biological processes that require careful control? Here, we highlight a selection of studies where CK2 activity is regulated at the substrate level, and discuss them based on the regulatory mechanism. Overall, this review describes numerous biological processes where CK2 activity is regulated, highlighting how a constitutively active kinase can still control numerous cellular activities. It is also evident that more research is required to fully elucidate the mechanisms that regulate CK2 and what causes aberrant CK2 signaling in disease. Full article
(This article belongs to the Special Issue CK2 Regulation of Cell Death and Targeting in Cancer Treatment)
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