CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression

Schmitt, B.; Boewe, Anne S; Götz, Claudia; Philipp, Stephan E.; Urbschat, Steffi; Oertel, Joachim; Menger, Michael D.; Laschke, Matthias W.; Ampofo, Emmanuel

doi:10.3390/cancers13071678

Cited by 13 publications

(16 citation statements)

References 54 publications

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“…With the advent of the CRISPR/Cas9 tool, it has been possible to produce viable knockout cancer cells for each CK2 catalytic subunit. Even if the production of these cells proved that the single individual catalytic CK2 subunit is not strictly required for cancer cell survival, these cells generally show a reduction in cell proliferation, motility/invasiveness, and an increase in sensitivity against chemotherapeutic agents when compared with wild-type cells [ 39 – 42 ]. Again, these effects are variably pronounced, according to the cell type and the target subunit gene.…”

Section: Non-pharmacological Ck2 Targeting Produces Antiproliferative and Pro-apoptotic Effects In Cancer Cellsmentioning

confidence: 99%

Targeting CK2 in cancer: a valuable strategy or a waste of time?

et al. 2021

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CK2 is a protein kinase involved in several human diseases (ranging from neurological and cardiovascular diseases to autoimmune disorders, diabetes, and infections, including COVID-19), but its best-known implications are in cancer, where it is considered a pharmacological target. Several CK2 inhibitors are available and clinical trials are underway in different cancer types. Recently, the suitability of CK2 as a broad anticancer target has been questioned by the finding that a newly developed compound, named SGC-CK2-1, which is more selective than any other known CK2 inhibitor, is poorly effective in reducing cell growth in different cancer lines, prompting the conclusion that the anticancer efficacy of CX-4945, the commonly used clinical-grade CK2 inhibitor, is to be attributed to its off-target effects. Here we perform a detailed scrutiny of published studies on CK2 targeting and a more in-depth analysis of the available data on SGC-CK2-1 vs. CX-4945 efficacy, providing a different perspective about the actual reliance of cancer cells on CK2. Collectively taken, our arguments would indicate that the pretended dispensability of CK2 in cancer is far from having been proved and warn against premature conclusions, which could discourage ongoing investigations on a potentially valuable drug target.

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Section: Non-pharmacological Ck2 Targeting Produces Antiproliferative and Pro-apoptotic Effects In Cancer Cellsmentioning

confidence: 99%

Targeting CK2 in cancer: a valuable strategy or a waste of time?

et al. 2021

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“…Further, mutation of the three serines (99,102,103) in the HMGA1 C-terminus disrupts invasive properties of the TNBC cell line. Intriguingly, CK2 inhibitors were also found to decrease tumor cell invasion in glioblastoma cell lines (GBM) [71][72][73][74]. A recent study using organotypic GBM experimental models also found that the transcriptional repressor interferon regulatory factor 3 (IRF3) decreases invasion in GBM cells [71].…”

Section: Hmga1 Secretion and Casein Kinase 2 (Ck2)mentioning

confidence: 99%

HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location!

Pujals¹,

Resar

Villanueva

2021

Biomolecules

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The gene encoding the High Mobility Group A1 (HMGA1) chromatin remodeling protein is upregulated in diverse cancers where high levels portend adverse clinical outcomes. Until recently, HMGA1 was assumed to be a nuclear protein exerting its role in cancer by transcriptionally modulating gene expression and downstream signaling pathways. However, the discovery of an extracellular HMGA1-RAGE autocrine loop in invasive triple-negative breast cancer (TNBC) cell lines implicates HMGA1 as a “moonlighting protein” with different functions depending upon cellular location. Here, we review the role of HMGA1, not only as a chromatin regulator in cancer and stem cells, but also as a potential secreted factor that drives tumor progression. Prior work found that HMGA1 is secreted from TNBC cell lines where it signals through the receptor for advanced glycation end products (RAGE) to foster phenotypes involved in tumor invasion and metastatic progression. Studies in primary TNBC tumors also suggest that HMGA1 secretion associates with distant metastasis in TNBC. Given the therapeutic potential to target extracellular proteins, further work to confirm this role in other contexts is warranted. Indeed, crosstalk between nuclear and secreted HMGA1 could change our understanding of tumor development and reveal novel therapeutic opportunities relevant to diverse human cancers overexpressing HMGA1.

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“…For Akt phosphorylation analysis, LNCaP cells were cultured in 6-well plates for 48 h. Afterward, cells were treated with either vehicle control (1% DMSO) or 5a-2, 5b-2, or CX-4945 at 20 µM for 24 h. The cells were detached from the culture plates using cell scrapers, sedimented by centrifugation at 700 × g and 4 °C for 5 min, washed with PBS, and lysed by suspending in 100 µL homogenization buffer (50 mM Tris/HCl (pH 7.5), 1 mM EDTA, 1 mM Na 3 VO 4 , 0.5 mM NaF, 0.1 mM PMSF, 1 mM benzamidine, and 1% Triton X-100). Akt and pAkt S129 were analyzed in the cell lysates by immunoblotting as described by Schmitt et al [45] using the following antibodies:…”

Section: Analysis Of Akt Phosphorylationmentioning

confidence: 99%

4,5,7‐Trisubstituted indeno[1,2‐b]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects

et al. 2021

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Highly pleiotropic and constitutively active protein kinase CK2 is a key target in cancer therapy, but only one small-molecule inhibitor has reached clinical trials-CX-4945. In this study, we present the indeno[1,2-b]indole derivative 5-isopropyl-4-methoxy-7-methyl-5,6,7,8-tetrahydroindeno[1,2-b] indole-9,10-dione (5a-2) that decreased the intracellular CK2 activity in A431, A549, and LNCaP tumor cell lines analogous to CX-4945 (> 75% inhibition at 20 µM) and similarly blocked CK2-specific Akt phosphorylation in LNCaP cells. Cellular uptake analysis demonstrated higher intracellular concentrations of 5a-2 (408.3 nM) compared with . This finding clarifies the comparable effects of both compounds on the intracellular CK2 activity despite their different inhibitory potency in vitro [IC 50 = 25 nM (5a-2) and 3.7 nM (CX-4945)]. Examination of the effects of both CK2 inhibitors on cancer cells using live-cell imaging revealed notable differences. Whereas CX-4945 showed a stronger pro-apoptotic effect on tumor cells, 5a-2 was more effective in inhibiting tumor cell migration. Our results showed that 49% of intracellular CX-4945 was localized in the nuclear fraction, whereas 71% of 5a-2 was detectable in the cytoplasm. The different subcellular distribution, and thus the site of CK2 inhibition, provides a possible explanation for the different cellular effects. Our study indicates that investigating CK2 inhibition-mediated cellular effects in relation to the subcellular sites of CK2 inhibition may help to improve our understanding of the preferential roles of CK2 within different cancer cell compartments.Human protein kinase CK2 is a constitutively active serine/threonine kinase [1]. Today, the enzyme, which was first described in 1954 as 'casein kinase 2', is known to phosphorylate more than 500 substrates [2,3]. Together with an ubiquitous expression in eukaryotic cells [4], this high pleiotropy is the reason

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CK2 Activity Mediates the Aggressive Molecular Signature of Glioblastoma Multiforme by Inducing Nerve/Glial Antigen (NG)2 Expression

Cited by 13 publications

References 54 publications

Targeting CK2 in cancer: a valuable strategy or a waste of time?

Targeting CK2 in cancer: a valuable strategy or a waste of time?

HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location!

4,5,7‐Trisubstituted indeno[1,2‐b]indole inhibits CK2 activity in tumor cells equivalent to CX‐4945 and shows strong anti‐migratory effects

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