CK2 Suppression of Apoptosis and Its Implication in Cancer Biology and Therapy

Trembley, Janeen H.; Wu, Jing; Unger, Gretchen M.; Kren, Betsy T.; Ahmed, Khalil

doi:10.1002/9781118482490.ch12

Cited by 18 publications

(19 citation statements)

References 139 publications

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“…Further, our demonstration that prior forced overexpression of CK2 in cells protected them from undergoing apoptosis mediated by etoposide and diethylstilbestrol provided direct evidence of the ability of CK2 to suppress apoptosis [Guo et al, 2001;Ahmed et al, 2002]. The now accepted role of CK2 as a suppressor of apoptosis is underscored by its impact on apoptosis mediated by diverse stimuli such as loss of survival factors (hormones, growth factors), chemical agents (drugs such as etoposide, diethylstilbestrol, inhibitors of CK2), death receptor mediated signals (such as TNFa, TRAIL, FasL), physical agents (such as heat, radiation), and molecular downregulation of CK2 [Guo et al, 1999[Guo et al, , 2001Wang et al, 2001;Ahmed et al, 2002;Davis et al, 2002;Yamane and Kinsella, 2005;Wang et al, 2005aWang et al, , 2006Ahmad et al, 2008;Wang et al, 2008;Trembley et al, 2011Trembley et al, , 2012Trembley et al, , 2013. These various observations prompted us to suggest that CK2 could serve as a cancer therapy target Slaton et al, 2004;Unger et al, 2004;Ahmad et al, 2005;Wang et al, 2005b]; the potential of CK2 as a target continues to gain broad acceptance with mounting evidence of its druggability for cancer therapy [Sarno and Pinna, 2008;Pinna and Allende, 2009].…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase CK2 Inhibition Induces Cell Death via Early Impact on Mitochondrial Function

Qaiser

Trembley

Kren

et al. 2014

J of Cellular Biochemistry

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CK2 (official acronym for casein kinase 2 or II) is a potent suppressor of apoptosis in response to diverse apoptotic stimuli —thus its molecular downregulation or activity inhibition results in potent induction of cell death. CK2 downregulation is known to impact mitochondrial apoptotic circuitry but the underlying mechanism(s) remain unclear. Utilizing prostate cancer cell lines subjected to CK2-specific inhibitors which cause loss of cell viability, we have found that CK2 inhibition in cells causes rapid early decrease in mitochondrial membrane potential (Δψm). Cells treated with the CK2 inhibitors TBB (4,5,6,7-tetrabromobenzotriazole) or TBCA (tetrabromocinnamic acid) demonstrate changes in Δψm which become apparent within 2 h, i.e., significantly prior to evidence of activation of other mitochondrial apoptotic signals whose temporal expression ensues subsequent to loss of Δψm. Further, we have demonstrated the presence of CK2 in purified mitochondria and it appears that the effect on Δψm evoked by inhibition of CK2 may involve mitochondrial localized CK2. Results also suggest that alterations in Ca2+ signaling may be involved in the CK2 mediated regulation of Δψm and mitochondrial permeability. Thus, we propose that a key mechanism of CK2 impact on mitochondrial apoptotic circuitry and cell death involves early loss of Δψm which may be a primary trigger for apoptotic signaling and cell death resulting from CK2 inhibition.

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Section: Discussionmentioning

confidence: 99%

Protein Kinase CK2 Inhibition Induces Cell Death via Early Impact on Mitochondrial Function

Qaiser

Trembley

Kren

et al. 2014

J of Cellular Biochemistry

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“…Previous work mainly focused on regulation of CK2 kinase activity and protein level and led to the conviction, that CK2 is a ubiquitously expressed, constitutively active kinase [46,47]. However, the CK2 kinase has also been shown to be a crucial constituent of tightly regulated cellular processes [48][49][50]. In addition, the expression and/or the activity of individual CK2 subunits seem to be controlled independently but very precisely.…”

Section: Discussionmentioning

confidence: 99%

CK2 kinase activity but not its binding to CK2 promoter regions is implicated in the regulation of CK2α and CK2β gene expressions

et al. 2013

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Protein kinase CK2, a ubiquitous serine/threonine kinase in control of a variety of crucial cellular functions, is composed of catalytic α- and α'-subunits and non-catalytic β-subunits which form holoenzymes such as CK2(αβ)2, CK2αα'β2, or CK2(α'β)2. In addition, there is ample evidence for the occurrence of the individual subunits beside the holoenzyme. While the CK2 subunits are well analyzed on the protein level, only little is known about the regulation of their transcription. The existence of multiple forms of CK2 subunits raised the question about a mutual regulation of their expression. Here we defined two 5'-upstream regions of the CK2α and the CK2β genes, respectively, as sequences with promoter activities. We found that CK2α and CK2α' stimulated the expression of the reporter constructs whereas, CK2β was inactive. Using chromatin immunoprecipitation assays, we were unable to detect binding of endogenous CK2 subunits to these promoter sequences in vivo. However, it turned out that inhibition of the kinase activity of CK2 attenuated the promoter activity indicating that CK2α and CK2α' might regulate their gene expression indirectly by phosphorylation reactions. Thus, we have shown here (i) that under normal physiological conditions CK2 does not bind to CK2 promoter regions and (ii) that the CK2 kinase activity is implicated in the regulation of its own expression.

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“…This increase in CK2 expression correlates with increased nuclear localization, is not associated with any mutational changes in CK2 genes, and serves as a prognostic indicator (5, 9). Its role in cancer cell biology likely relates to its interaction with various hallmarks of cancer (7, 40, 41), and we originally proposed CK2 as a potentially important target for cancer therapy (14). Since then, much evidence has come forth to support CK2 as a druggable target (20, 21, 42).…”

Section: Discussionmentioning

confidence: 99%

Mechanism and Efficacy of Sub–50-nm Tenfibgen Nanocapsules for Cancer Cell–Directed Delivery of Anti-CK2 RNAi to Primary and Metastatic Squamous Cell Carcinoma

Unger¹,

Kren

Korman³

et al. 2014

Molecular Cancer Therapeutics

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Improved survival for HNC patients with recurrent and metastatic disease warrants that cancer therapy is specific with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub-50 nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell-specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA induced silencing complex (Ago2/RISC) pathway to target the CK2αα' mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft head and neck squamous cell carcinoma (HNSCC) models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise.

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CK2 Suppression of Apoptosis and Its Implication in Cancer Biology and Therapy

Cited by 18 publications

References 139 publications

Protein Kinase CK2 Inhibition Induces Cell Death via Early Impact on Mitochondrial Function

Protein Kinase CK2 Inhibition Induces Cell Death via Early Impact on Mitochondrial Function

CK2 kinase activity but not its binding to CK2 promoter regions is implicated in the regulation of CK2α and CK2β gene expressions

Mechanism and Efficacy of Sub–50-nm Tenfibgen Nanocapsules for Cancer Cell–Directed Delivery of Anti-CK2 RNAi to Primary and Metastatic Squamous Cell Carcinoma

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