AccScience Publishing / TD / Online First / DOI: 10.36922/td.4571
ORIGINAL RESEARCH ARTICLE

Deregulation of Casein Kinase-2 in non-small-cell lung cancer: A subunit-specific analysis

George V. Pérez1,2 Chen Li3 Chenyi Deng4 Ying Yi5 Qiang Zhao4 Zhiwei Zhang3 Wen Li5* Silvio E. Perea1* Yasser Perera1,5*
Show Less
1 Department of Pharmaceuticals, Biomedical Research Division, Center for Genetic Engineering and Biotechnology, Havana, Cuba
2 Department of Biochemistry and Molecular Biology, Complutense, Madrid, Spain
3 Key Laboratory of Cancer Cellular and Molecular Pathology, Cancer Research Institute of Hengyang Medical School, University of South China, Hengyang, Hunan, People’s Republic of China
4 Department of Pathology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, People’s Republic of China
5 China-Cuba Biotechnology Joint Innovation Center, Yongzhou Development and Construction Investment Co., Ltd., Yongzhou, Hunan, People’s Republic of China
Tumor Discovery, 4571 https://doi.org/10.36922/td.4571
Submitted: 19 August 2024 | Accepted: 17 October 2024 | Published: 29 November 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Casein kinase-2 (CK2) is a constitutively active kinase that supports neoplastic properties. Although there is an extensive body of preclinical research on CK2, translational and clinical information remains limited and sparse. In this study, we interrogated clinical multiomics databases to examine CK2 deregulation across various cancers. Specifically, we analyzed the mutational frequency, copy-number alterations (CNA), and mRNA expression of CK2 catalytic (CSNK2A1 and CSNK2A2) and regulatory (CSNK2B) subunits across two major cancer genomic repositories (The Cancer Genome Atlas/International Cancer Genome Consortium). These genomic and transcriptomic analyses were further focused on lung cancer and complemented by in situ assessments of CK2 protein subunits and enzymatic activity in biopsies from non-small-cell lung cancer (NSCLC). Our findings indicate that gene mutations and CNA do not account for the elevated mRNA levels and enzymatic activity of CK2 subunits in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Particularly, the upregulation of CSNK2A1 and CSNK2B mRNA was associated with a worse prognosis and showed a direct correlation with the infiltration of myeloid-derived suppressor cells in LUAD. At the protein levels, all CK2 subunits and enzymatic activity were markedly elevated in LUAD (n = 103) and LUSC (n = 31) biopsies; however, only CSNK2A1 expression correlated positively with tumor size and disease stage. Finally, CSNK2A1 appeared to be more tumor-specific than CSNK2A2, suggesting that targeted therapies against this catalytic subunit or its homotetramer may offer a more favorable therapeutic window in NSCLC.

Keywords
Casein Kinase-2
Casein kinase-2 regulation
Lung cancer
Translational study
Oncology target
Funding
This research was supported by the National Key R&D Program of China (2021YFE0192100).
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Ruzzene M, Pinna LA. Addiction to protein kinase CK2: A common denominator of diverse cancer cells? Biochim Biophys Acta. 2010;1804(3):499-504. doi: 10.1016/j.bbapap.2009.07.018

 

  1. Borgo C, Franchin C, Cesaro L, et al. A Proteomics analysis of CK2β(-/-) C2C12 Cells provides novel insights into the biological functions of the non-catalytic β subunit. FEBS J. 2019;286(8):1561-1575. doi: 10.1111/febs.14799

 

  1. Roffey SE, Litchfield DW. CK2 regulation: Perspectives in 2021. Biomedicines. 2021;9(10):1361. doi: 10.3390/biomedicines9101361

 

  1. Trembley JH, Kren BT, Afzal M, Scaria GA, Klein MA, Ahmed K. Protein kinase CK2- diverse roles in cancer cell biology and therapeutic promise. Mol Cell Biochem. 2023;478(4):899-926. doi: 10.1007/s11010-022-04558-2

 

  1. Borgo C, D’Amore C, Cesaro L, et al. How can a traffic light properly work if it is always green? The paradox of CK2 signaling. Crit Rev Biochem Mol Biol. 2021;56(4):321-359. doi: 10.1080/10409238.2021.1908951

 

  1. Salvi M, Borgo C, Pinna LA, Ruzzene M. Targeting CK2 in cancer: A valuable strategy or a waste of time? Cell Death Discov. 2021;7(1):325. doi: 10.1038/s41420-021-00717-4

 

  1. Wells CI, Drewry DH, Pickett JE, et al. Development of a potent and selective chemical probe for the pleiotropic kinase CK2. Cell Chem Biol. 2021;28(4):546-558.e10. doi: 10.1016/j.chembiol.2020.12.013

 

  1. Licciardello MP, Workman P. A New chemical probe challenges the broad cancer essentiality of CK2. Trends Pharmacol Sci. 2021;42(5):313-315. doi: 10.1016/j.tips.2021.02.002

 

  1. Cozza G. The development of CK2 inhibitors: From traditional pharmacology to in silico rational drug design. Pharmaceuticals (Basel). 2017;10(1):26. doi: 10.3390/ph10010026

 

  1. Bancet A, Frem R, Jeanneret F, et al. AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1. bioRxiv [Preprint]. 2022. doi: 10.1101/2022.12.16.520736

 

  1. Solares AM, Santana A, Baladrón I, et al. Safety and preliminary efficacy data of a novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies. BMC Cancer. 2009;9:146. doi: 10.1186/1471-2407-9-146

 

  1. Pierre F, Chua PC, O’Brien SE, et al. Discovery and SAR of 5-(3-chlorophenylamino)benzo[c][2,6naphthyridine-8- carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer. J Med Chem. 2011;54(2):635-654. doi: 10.1021/jm101251q

 

  1. Strum SW, Gyenis L, Litchfield DW. CSNK2 in cancer: Pathophysiology and translational applications. Br J Cancer. 2022;126(7):994-1003. doi: 10.1038/s41416-021-01616-2

 

  1. Cerami E, Gao J, Dogrusoz U, et al. The CBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404. doi: 10.1158/2159-8290.CD-12-0095

 

  1. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the CBioPortal. Sci Signal. 2013;6(269):pl1. doi: 10.1126/scisignal.2004088

 

  1. Martínez-Jiménez F, Muiños F, Sentís I, et al. A compendium of mutational cancer driver genes. Nat Rev Cancer. 2020;20(10):555-572. doi: 10.1038/s41568-020-0290-x

 

  1. Chakravarty D, Gao J, Phillips SM, et al. OncoKB: A precision oncology knowledge base. JCO Precis Oncol. 2017;1:1-16. doi: 10.1200/PO.17.00011

 

  1. Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8): 649-658. doi: 10.1016/j.neo.2017.05.002

 

  1. Cai L, Lin S, Girard L, et al. LCE: An open web portal to explore gene expression and clinical associations in lung cancer. Oncogene. 2019;38(14):2551-2564. doi: 10.1038/s41388-018-0588-2

 

  1. Bartha Á, Győrffy B. TNMplot.Com: A web tool for the comparison of gene expression in normal, tumor and metastatic tissues. Int J Mol Sci. 2021;22(5):2622. doi: 10.3390/ijms22052622

 

  1. Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509-W514. doi: 10.1093/nar/gkaa407

 

  1. TCGA Research Network. Available from: https://www. cancer.gov/tcga [Last accessed: November 27, 2024]

 

  1. ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020;578(7793):82-93. doi: 10.1038/s41586-020-1969-6

 

  1. Firnau MB, Brieger A. CK2 and the hallmarks of cancer. Biomedicines. 2022;10(8):1987. doi: 10.3390/biomedicines10081987

 

  1. Chua MMJ, Ortega CE, Sheikh A, et al. CK2 in cancer: Cellular and biochemical mechanisms and potential therapeutic target. Pharmaceuticals (Basel). 2017;10(1):18. doi: 10.3390/ph10010018

 

  1. Ortega CE, Seidner Y, Dominguez I. Mining CK2 in cancer. PLoS One. 2014;9(12):e115609. doi: 10.1371/journal.pone.0115609

 

  1. Chua MMJ, Lee M, Dominguez I. Cancer-type dependent expression of CK2 transcripts. PLoS One. 2017;12(12):e0188854. doi: 10.1371/journal.pone.0188854

 

  1. Filhol O, Giacosa S, Wallez Y, Cochet C. Protein kinase CK2 in breast cancer: The CK2β regulatory subunit takes center stage in epithelial plasticity. Cell Mol Life Sci. 2015;72(17):3305-3322. doi: 10.1007/s00018-015-1929-8

 

  1. Litchfield DW, Bosc DG, Canton DA, Saulnier RB, Vilk G, Zhang C. Functional specialization of CK2 isoforms and characterization of isoform-specific binding partners. Mol Cell Biochem. 2001;227(12):21-29.

 

  1. Zonta F, Borgo C, Quezada Meza CP, et al. Contribution of the CK2 catalytic isoforms α and α’ to the glycolytic phenotype of tumor cells. Cells. 2021;10(1):181. doi: 10.3390/cells10010181

 

  1. Ackermann K, Neidhart T, Gerber J, Waxmann A, Pyerin W. The catalytic subunit alpha’ gene of human protein kinase CK2 (CSNK2A2): Genomic organization, promoter identification and determination of Ets1 as a key regulator. Mol Cell Biochem. 2005;274(1-2):91-101. doi: 10.1007/s11010-005-3076-2

 

  1. Sheida F, Razi S, Keshavarz-Fathi M, Rezaei N. The role of myeloid-derived suppressor cells in lung cancer and targeted immunotherapies. Expert Rev Anticancer Ther. 2022;22(1):65-81. doi: 10.1080/14737140.2022.2011224

 

  1. Chen C, Hou J, Yu S, et al. Role of cancer-associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non-small cell lung cancer. Oncol Lett. 2021;21(5):413. doi: 10.3892/ol.2021.12674

 

  1. Wu F, Yang J, Liu J, et al. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther. 2021;6(1):218. doi: 10.1038/s41392-021-00641-0

 

  1. Glabman RA, Choyke PL, Sato N. Cancer-associated fibroblasts: Tumorigenicity and targeting for cancer therapy. Cancers (Basel). 2022;14(16):3906. doi: 10.3390/cancers14163906

 

  1. Umansky V, Blattner C, Gebhardt C, Utikal J. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines (Basel). 2016;4(4):36. doi: 10.3390/vaccines4040036

 

  1. Daya-Makin M, Sanghera JS, Mogentale TL, et al. Activation of a tumor-associated protein kinase (P40TAK) and casein kinase 2 in human squamous cell carcinomas and adenocarcinomas of the lung. Cancer Res. 1994;54(8): 2262-2268.

 

  1. Yaylim I, Isbir T. Enhanced casein kinase II (CK II) activity in human lung tumours. Anticancer Res. 2002;22(1A): 215-218.

 

  1. Liu Y, Amin EB, Mayo MW, et al. CK2α’ drives lung cancer metastasis by targeting BRMS1 nuclear export and degradation. Cancer Res. 2016;76(9):2675-2686. doi: 10.1158/0008-5472.CAN-15-2888

 

  1. Xie ZC, Tang RX, Gao X, et al. A meta-analysis and bioinformatics exploration of the diagnostic value and molecular mechanism of mir-193a-5p in lung cancer. Oncol Lett. 2018;16(4):4114-4128. doi: 10.3892/ol.2018.9174

 

  1. Cesaro L, Zuliani AM, Travain VB, Salvi M. Exploring protein kinase CK2 substrate recognition and the dynamic response of substrate phosphorylation to kinase modulation. Kinases Phosphatases. 2023;1(4):251-264. doi: 10.3390/kinasesphosphatases1040015

 

  1. Tsherniak A, Vazquez F, Montgomery PG, et al. Defining a cancer dependency map. Cell. 2017;170(3):564-576.e16. doi: 10.1016/j.cell.2017.06.010
Share
Back to top
Tumor Discovery, Electronic ISSN: 2810-9775 Print ISSN: 3060-8597, Published by AccScience Publishing