Stem Cell-Like Properties of CK2β-down Regulated Mammary Cells

Duchemin-Pelletier, Eve; Baulard, Megghane; Spreux, Elodie; Prioux, Magali; Burute, Mithila; Mograbi, Baharia; Guyon, Laurent; Théry, Manuel; Cochet, Claude; Filhol, Odile

doi:10.3390/cancers9090114

Cited by 6 publications

(5 citation statements)

References 56 publications

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“…Furthermore, inhibition of CK2 activity with TBB decreases cell viability and proliferation in MCF-7 breast cancer cells, which correlates with changes in different miRNAs (34). Likewise, CK2β knockdown leads to downregulation of different miRNAs related to cellular processes such as EMT and invasion in MCF10A breast epithelial cells (35). Nevertheless, whether the CK2-related miRNAs are successful in modulating metabolism and bioenergetics in cancer cells remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase CK2 in Cancer Energetics

Silva-Pavez

Tapia

2020

Front. Oncol.

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Protein kinase CK2 (formerly known as casein kinase 2) is abnormally elevated in many cancers. This may increase tumor aggressiveness through CK2-dependent phosphorylation of key proteins in several signaling pathways. In this work, we have compiled evidence from the literature to suggest that CK2 also modulates a metabolic switch characteristic of cancer cells that enhances resistance to death, due to either drugs or to a microenvironment deficient in oxygen or nutrients. Concurrently, CK2 may help to preserve mitochondrial activity in a PTEN-dependent manner. PTEN, widely recognized as a tumor suppressor, is another CK2 substrate in the PI3K/Akt signaling pathway that promotes cancer viability and aerobic glycolysis. Given that CK2 can regulate Akt as well as two of its main effectors, namely mTORC1 and β-catenin, we comprehensively describe how CK2 may modulate cancer energetics by regulating expression of key targets and downstream processes, such as HIF-1 and autophagy, respectively. Thus, the specific inhibition of CK2 may lead to a catastrophic death of cancer cells, which could become a feasible therapeutic strategy to beat this devastating disease. In fact, ATP-competitive inhibitors, synthetic peptides and antisense oligonucleotides have been designed as CK2 inhibitors, some of them used in preclinical models of cancer, of which TBB and silmitasertib are widely known. We will finish by discussing a hypothetical scenario in which cancer cells are "addicted" to CK2; i.e., in which many proteins that regulate signaling pathways and metabolism-linked processes are highly dependent on this kinase.

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Section: Introductionmentioning

confidence: 99%

Protein Kinase CK2 in Cancer Energetics

Silva-Pavez

Tapia

2020

Front. Oncol.

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“…Interestingly, a sub-stoichiometric expression of CK2β compared to CK2α in a subset of breast cancer tumors is correlated with the induction of hypoxia and epithelial to mesenchymal transition (EMT) markers, providing evidence that unbalanced expression of CK2 subunits may influence key cellular processes associated with epithelial cell plasticity in breast carcinoma progression ( Deshiere et al, 2013 ; Golden and Cantley, 2014 ). We further demonstrate that CK2β depletion in non-transformed mammary epithelial cells induced dissociation of cell–cell contacts, led to the acquisition of a mesenchymal cell shape (properties described for EMT-induced cells), and drove breast cell stemness ( Deshiere et al, 2008 ; Deshiere et al, 2011 ; Deshiere et al, 2013 ; Golden and Cantley, 2014 ; Filhol et al, 2015 ; Duchemin-Pelletier et al, 2017 ). These disparate effects may be dependent on the levels of free CK2α, which is markedly elevated in metastatic tumors compared to non-transformed cells ( Kim et al, 2007 ; Laramas et al, 2007 ; Giusiano et al, 2011 ; Lin et al, 2011 ; Roelants et al, 2015 ; Choy et al, 2017 ; Schmitt et al, 2021 ).…”

Section: Introductionmentioning

confidence: 57%

“…Given the interplay between serine/threonine and tyrosine kinases, we evaluated the potential impact of an imbalanced expression of CK2 subunits on global tyrosine kinase activity in WT non-transformed mammary MCF10A or shRNA-mediated CK2β-silenced MCF10A cells (ΔCK2β) ( Deshiere et al, 2013 ; Deshiere et al, 2011 ; Deshiere et al, 2008 ; Filhol et al, 2015 ; Duchemin-Pelletier et al, 2017 ; Golden and Cantley, 2014 ). For this purpose, we used the PamChip PTK multiplex activity profiling (PamGene International BV ’s-Hertogenbosch, Netherlands).…”

Section: Resultsmentioning

confidence: 99%

CK2β Is a Gatekeeper of Focal Adhesions Regulating Cell Spreading

Filhol

Hesse

Bouin

et al. 2022

Front. Mol. Biosci.

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CK2 is a hetero-tetrameric serine/threonine protein kinase made up of two CK2α/αʹ catalytic subunits and two CK2β regulatory subunits. The free CK2α subunit and the tetrameric holoenzyme have distinct substrate specificity profiles, suggesting that the spatiotemporal organization of the individual CK2 subunits observed in living cells is crucial in the control of the many cellular processes that are governed by this pleiotropic kinase. Indeed, previous studies reported that the unbalanced expression of CK2 subunits is sufficient to drive epithelial to mesenchymal transition (EMT), a process involved in cancer invasion and metastasis. Moreover, sub-stoichiometric expression of CK2β compared to CK2α in a subset of breast cancer tumors was correlated with the induction of EMT markers and increased epithelial cell plasticity in breast carcinoma progression. Phenotypic changes of epithelial cells are often associated with the activation of phosphotyrosine signaling. Herein, using phosphotyrosine enrichment coupled with affinity capture and proteomic analysis, we show that decreased expression of CK2β in MCF10A mammary epithelial cells triggers the phosphorylation of a number of proteins on tyrosine residues and promotes the striking activation of the FAK1-Src-PAX1 signaling pathway. Moreover, morphometric analyses also reveal that CK2β loss increases the number and the spatial distribution of focal adhesion signaling complexes that coordinate the adhesive and migratory processes. Together, our findings allow positioning CK2β as a gatekeeper for cell spreading by restraining focal adhesion formation and invasion of mammary epithelial cells.

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“…CK2 has emerged as a possible regulator of cancer stem cell (CSC) genes [103, 104]. Down-regulation of CK2β in epithelial cells induces the acquisition of stem cell-like properties [105], and CK2 inhibition significantly affects the neural stem cell niche [106]. A major role of CK2 has been found in the functions of glioblastoma brain tumor initiating cells (BTICs) [107].…”

Section: Main Textmentioning

confidence: 99%

Role of protein kinase CK2 in antitumor drug resistance

Borgo

Ruzzene

2019

J Exp Clin Cancer Res

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Drug resistance represents the major reason of pharmacological treatment failure. It is supported by a broad spectrum of mechanisms, whose molecular bases have been frequently correlated to aberrant protein phosphorylation. CK2 is a constitutively active protein kinase which phosphorylates hundreds of substrates; it is expressed in all cells, but its level is commonly found higher in cancer cells, where it plays anti-apoptotic, pro-migration and pro-proliferation functions. Several evidences support a role for CK2 in processes directly responsible of drug resistance, such as drug efflux and DNA repair; moreover, CK2 intervenes in signaling pathways which are crucial to evade drug response (as PI3K/AKT/PTEN, NF-κB, β-catenin, hedgehog signaling, p53), and controls the activity of chaperone machineries fundamental in resistant cells. Interestingly, a panel of specific and effective inhibitors of CK2 is available, and several examples are known of their efficacy in resistant cells, with synergistic effect when used in combination with conventional drugs, also in vivo. Here we analyze and discuss evidences supporting the hypothesis that CK2 targeting represents a valuable strategy to overcome drug resistance.

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Stem Cell-Like Properties of CK2β-down Regulated Mammary Cells

Cited by 6 publications

References 56 publications

Protein Kinase CK2 in Cancer Energetics

Protein Kinase CK2 in Cancer Energetics

CK2β Is a Gatekeeper of Focal Adhesions Regulating Cell Spreading

Role of protein kinase CK2 in antitumor drug resistance

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