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Tumor Discovery CK2 deregulation in non-small-cell lung cancer

accumulation within the tumor microenvironment. 32-36 In indicate that CSNK2A1 protein is more tumor-specific
summary, based on mRNA expression data, we consistently than CSNK2A2. Interestingly, a preliminary in vitro
observed CSNK2A1 and CSNK2B overexpression, assessment of dependency scores from knocking out
associations with survival and metastasis, and stronger (CRISPR-Chronos) individual CSNK2 genes in 98 NSCLC
correlations with tumor-infiltrating MDSC, particularly cell lines suggests that CSNK2A1-KO is approximately
in LUAD samples. Although internal correlations among 10-fold more “essential” than CSNK2A2-KO in these lung
CSNK2 subunits may pose some analysis bias, we did not cancer models (https://depmap.org/portal/). 42
detect significant internal correlations between CSNK2A1
and CSNK2B. Furthermore, correlations between the 5. Conclusion
catalytic subunits were weaker in LUAD (S = 0.14) than in Our data suggest that transcriptional regulatory
LUSC (S = 0.24) across analyzed cohorts. mechanisms, rather than mutational and CNA events,
On the other hand, protein information concerning drive the increased mRNA expression of CK2 subunits
CK2 subunits and enzymatic activity in human lung in NSCLC samples. Correspondingly, CK2 subunits and
specimens is limited. Strum et al. reviewed four studies enzymatic activity are significantly upregulated in NSCLC,
13
measuring overall CK2 levels or activity in LUAD and/ particularly in LUSC. Correlative studies at both mRNA
39
or LUSC samples. 37-40 In one of these studies, Liu et al. and protein levels indicate that CSNK2A1, and potentially
analyzed CSNK2A2 subunit expression in 160 NSCLC its homotetramer (CSNK2A1 /CSNK2B ), may exert
2
2
patients, finding it upregulated in both LUAD and LUSC specific tumor-supportive functions in LUAD. These
and marginally associated with reduced OS. In our studies, compelling yet correlative findings highlight the potential
we observed elevated protein levels for all three CK2 need for isoform-specific CK2-targeted therapies and may
subunits in LUAD and LUSC specimens. More importantly, further elucidate CK2’s role in NSCLC on the development
we demonstrate that this upregulation correlates with of tailored drugs against specific CSNK2 isoforms or
increased enzymatic activity in situ, as indicated by CK2 homotetramers.
substrates predominantly localized in the cytoplasm Acknowledgments
(AKT) or nucleus (NPM1) of the cell. Notably, the catalytic
subunits CSNK2A1 and CSNK2A2, and their purported The results published here are partly based on data
enzymatic activity (as suggested by pAKT levels), were generated by the TCGA Research Network (https://www.
higher in LUSC than in LUAD specimens. We consider the cancer.gov/tcga). We also thank assistant researchers
canonical AKTs129 (pAKT) phosphorylation site a more and technicians from the First Affiliated Hospital of the
reliable surrogate marker for CK2 in situ activity in tumors University of South China.
compared to NPM1s125 (pNPM1). The differing extents Funding
13
of AKT and NPM1 phosphorylation could be explained by
variations in phosphorylation turnover for each substrate This research was supported by the National Key R&D
and phosphorylation site within CK2 signaling, potentially Program of China (2021YFE0192100).
faster for AKT. Finally, CSNK2A1 and CSNK2A2
41
expression correlated strongly and positively with NPM1 Conflict of interest
(but not AKT), underscoring the complex interplay The authors declare that they have no competing interests.
among kinase-phosphatase activities, CK2 substrates, and
subcellular compartments. 41 Author contributions
Importantly, CSNK2A1 (but not CSNK2A2) protein Conceptualization: George V. Pérez, Yasser Perera
overexpression correlates with tumor size, stage, and Investigation: All authors
proliferation score in the NSCLC tumors analyzed. This Methodology: George V. Pérez, Qiang Zhao, Zhiwei Zhang,
subunit-specific association is evident despite positive Yasser Perera
internal correlations between both catalytic subunits at Writing – original draft: Yasser Perera
the protein (R≈0.5) and mRNA levels (R≈0.2) across Writing – review & editing: George V. Pérez
independent cohorts. Notably, at the protein level, context-
dependent regulatory crosstalk occurs among CK2 Ethics approval and consent to participate
subunits, reflecting overlapping activities and, in some Studies involving human specimens were conducted in
instances, isoforms-specific functions. Therefore, our accordance with ethical principles from the Helsinki
3
findings suggest that CSNK2A1 may play a distinctive Declaration (2013), the Regulations on Biomedical Ethics
role in NSCLC. Supporting this notion, our IHC studies Review Involving Humans (2016), the Regulations on

Volume 3 Issue 4 (2024) 11 doi: 10.36922/td.4571