The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies

Chon, Hae Jung; Bae, Kyoung Jun; Lee, Yura; Kim, Jiyeon

doi:10.3389/fphar.2015.00070

Cited by 102 publications

(94 citation statements)

References 53 publications

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“…Importantly, our data suggest that CK2 inhibitors may prove useful as therapeutic agents for the treatment of T2D. It should also be noted that CX-4945, also known as silmitasertib, has shown great potential as an anticancer agent in several clinical trials (35). For these reasons, the data reported here should be of considerable clinical interest.…”

Section: Discussionmentioning

confidence: 55%

CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

Rossi

Azúa

Barella

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic β-cells. β-Cell M 3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of β-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic β-cells, knockdown of CK2α expression, or genetic deletion of CK2α in β-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonistinduced phosphorylation of β-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R-stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R-dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on β-cell GPCRs may represent novel therapeutic targets.G protein-coupled receptors | β-cell function | mouse models | glucose homeostasis | GPCR regulation

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Section: Discussionmentioning

confidence: 55%

CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

Rossi

Azúa

Barella

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Of the five small molecule kinase inhibitors studied here, the CK2 inhibitor CX-4945 scored second highest on the central nervous system multiparameter optimization (CNS MPO) algorithm for brain penetrance (Wager et al, 2010) (Table S3). Moreover, CX-4945 is the only one of the five drugs currently in clinical trials (Chon et al, 2015). Accordingly, our studies with this tumor model focused on CX-4945.…”

Section: Resultsmentioning

confidence: 99%

A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

et al. 2017

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SUMMARY During development of the vertebrate central nervous system, the bHLH transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here we identify a set of three serine/threonine protein kinases (GSK3α/β, CK2 and CDK1/2) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged “acid blob” in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward feeding phosphorylation cascade have potential as glioma therapeutics.

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“…The expression level and activity of CK2 are elevated in many cancers originating from diverse tissues (40). CK2 exhibits cell-proliferative and anti-apoptotic properties, and is thus attracting increasing attention as a promising target for cancer treatment (34,40). CK2 inhibitors such as CX-4945 are expected to decrease ceramide levels by inhibiting CERS phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Sassa

Hirayama

Kihara

2016

Journal of Biological Chemistry

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Ceramide and complex sphingolipids regulate important cellular functions including cell growth, apoptosis, and signaling. Dysregulation of sphingolipid metabolism leads to pathological consequences such as sphingolipidoses and insulin resistance. Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. In the present study, we demonstrated that CERS2-6 were phosphorylated at the cytoplasmic C-terminal regions. Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing its V max value. Phosphorylation modestly increased the catalytic activities of CERS4 and -5 and mildly increased those of CERS3 and -6. Dephosphorylation of endogenous ceramide synthases in the mouse brain led to severely reduced activity toward the Cers2 substrates C22:0/C24:0-CoAs and modestly reduced activity toward the Cers5/6 substrate C16:0-CoA. These results suggest that the phosphorylation of ceramide synthases may be a key regulatory point in the control of the distribution and levels of sphingolipids of various acyl-chain lengths.Sphingolipids, one of the major lipid constituents of eukaryotic membranes, mediate a number of cellular and physiological functions such as cell growth, apoptosis, immune responses, and the epidermal permeability barrier, whereas their abnormal metabolism is involved in diseases such as sphingolipidoses, neural disorders, and diabetes (1-7). Ceramides are located in the hub of sphingolipid metabolism. Ceramides are precursors for complex sphingolipids, whereas their hydrolysis releases a sphingoid long-chain base and a fatty acid (FA).2 The released long-chain base can then be recycled to synthesize new ceramide, or metabolized further into other lipids such as sphingosine 1-phosphate (8 -10). Ceramide synthases catalyze the formation of an amide bond between the long-chain base and the FA in the endoplasmic reticulum. In most tissues, the chain lengths of the FA moieties of ceramides are C16 -

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The casein kinase 2 inhibitor, CX-4945, as an anti-cancer drug in treatment of human hematological malignancies

Cited by 102 publications

References 53 publications

CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo

A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

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