Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy

Artesi, Maria; Kroonen, Jérôme; Bredel, Markus; Nguyen-Khac, M.T.; Deprez, Manuel; Schoysman, Laurent; Poulet, Christophe; Chakravarti, Arnab; Kim, Hyunsoo; Scholtens, Denise M.; Seute, Tatjana; Rogister, Bernard; Bours, Vincent; Robe, Pierre A.

doi:10.1093/neuonc/nou215

Cited by 38 publications

(43 citation statements)

References 77 publications

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“…Furthermore, in our proprietary series of gliomas, we observed that the CK2 kinase activity is high in gliomas independently from GBM class, glioma histology or grade, and that this kinase activity does not correlate with CNAs of any of the genes that code for the CK2 subunits or for classical regulators of CK2 activity, namely TGF-β receptors 1 and 2, PKC-ζ, α and β, or p38 MAPK. Of note however, we previously observed that the activity of CK2α is modulated in malignant gliomas by the expression of connexin 30, a tumor suppressor encoded by GJB6 (20). We likewise observed here that TNF-α, as well as TGF-β1, which are secreted in the microenvironment of gliomas (21)(22)(23), can induce the activity of CK2α and might thus contribute to its hyperactivity in gliomas.…”

Section: Discussionsupporting

confidence: 73%

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Dubois

Willems

Nguyen-Khac

et al. 2016

International Journal of Oncology

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Abstract. Casein kinase II contributes to the growth and survival of malignant gliomas and attracts increasing attention as a therapeutic target in these tumors. Several reports have suggested that this strategy might be most relevant for specific subgroups of patients, namely Verhaak's classical and TP53 wild-type tumors. Using kinase assays and microarray genetic profiling in a series of 27 proprietary fresh frozen surgical glioma samples, we showed that constitutive CK2 kinase activation is not restricted to tumors that present increased copy numbers or mRNA expression of its catalytic or regulatory subunits, and can result from a functional activation by various cytokines from the glioma microenvironment. Using corresponding primary tumor and human astrocyte cell cultures as well as glioma cell lines, we confirmed that CK2 inhibition is selectively toxic to malignant glial tumors, without any restriction to tumor class or to TP53 status. We finally showed that while the contribution of CK2 to the constitutive NF-κB hyperactivation in malignant gliomas is at best moderate, a delayed activation of NF-κB may associate with the therapeutic resistance of glioma cells to CK2 inhibition. IntroductionGlioblastomas (GBMs) are the most aggressive and prevalent type of primary brain tumors and present a dismal prognosis with a median survival of less than two years (1).Casein kinase 2 is a ubiquitous serine/threonine tetrameric kinase that consists of two catalytic subunits (α and α') and two β regulatory subunits. CK2 is frequently overexpressed or overactive in aggressive forms of solid and hematological malignancies (2,3), and contributes to the dysregulation of cell growth, invasion, survival and senescence via the β-catenin, JAK/STAT, mTOR, and NF-κB pathways (4-9). As a result, CK2 inhibitors have recently entered preliminary clinical trials for advanced solid and hematological tumors (source: ClinicalTrial.gov, accessed in December 2015).In GBMs, CSNK2A1, the gene encoding the α catalytic subunit of the kinase, is amplified in one third of the tumors, and especially in those that belong to the Verhaak's 'classical' gene expression phenotype (10). CK2 has been reported to regulate tumor-initiating cell growth, tumor cell survival, DNA repair following ionizing radiation, and apoptosis in these tumors (4,5,7,8,(11)(12)(13). As a result, CK2 inhibition with drug inhibitors or siRNA technology was shown to alter the growth, survival and migration of glioma cell lines and slow down the growth of GBMs xenografts in immunodeficient mice (9,14).Prior to translating these findings to the bedside however, it remains unclear whether CK2 hyperactivity is restricted to classical GBMs presenting a CSNK2A1 amplification or not and/or whether all malignant glial tumors are evenly likely to benefit from CK2 inhibitory strategies.This report provides evidence that CK2 kinase hyperactivity occurs in vivo in all classes of GBMs as well as in glial tumors of lower grades and histology, and can be a target independently of Verhaak's ...

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Section: Discussionsupporting

confidence: 73%

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Dubois

Willems

Nguyen-Khac

et al. 2016

International Journal of Oncology

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“…Studies in the early 1980’s showed a clear association between increased GJIC and resistance to radiotherapy, specifically in three-dimensional (3D) culture conditions 148 . Supporting this notion a recent study showed that, although restoration of Cx30 expression reduced growth of glioblastoma cell lines, it indeed conferred resistance to γ-radiation 149 . Nevertheless, in patient cohorts treated with radiation therapy, expression of Cx30 was associated with increased mortality 149 .…”

Section: Reassessing Connexins In Cancermentioning

confidence: 86%

“…Supporting this notion a recent study showed that, although restoration of Cx30 expression reduced growth of glioblastoma cell lines, it indeed conferred resistance to γ-radiation 149 . Nevertheless, in patient cohorts treated with radiation therapy, expression of Cx30 was associated with increased mortality 149 . Taken as a whole, stratification of tumour subtype, stage, and heterogeneity with connexin isoform profiles should be carried out to delineate connexin function in cancer.…”

Section: Reassessing Connexins In Cancermentioning

confidence: 86%

“…Cx43 downregulation was also shown to affect the cytoprotective properties of tumour cells by causing enhanced sensitivity and mitochondria-mediated apoptosis in response to low dose γ-radiation 178 . Mitochondrial translocation of Cx30 also appears to provide γ-radiation-resistance in human glioblastoma cells 149 . Going forward, additional studies are needed to determine if targeting the mitochondria-connexin relationship would have any putative therapeutic potential.…”

Section: Reassessing Connexins In Cancermentioning

confidence: 99%

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Gap junctions and cancer: communicating for 50 years

et al. 2016

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Fifty years ago, tumour cells were found to lack electrical coupling, leading to the hypothesis that loss of direct intercellular communication is commonly associated with cancer onset and progression. Subsequent studies linked this phenomenon to gap junctions composed of connexin proteins. While many studies support the notion that connexins are tumour suppressors, recent evidence suggests that, in some tumour types, they may facilitate specific stages of tumour progression through both junctional and non-junctional signalling pathways. This Timeline article highlights the milestones connecting gap junctions to cancer, and underscores important unanswered questions, controversies and therapeutic opportunities in the field.

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“…In both cell types Cx43 forms majority of gap junction channels and are responsible for spermine-mediated enhancement of the gap junctional communication. A172 glioblastoma cells are originated from glia cells, and can express several connexines [23, 24]. However, our studies revealed that knock-down of Cx43 in human glioma cells eliminated not only spermine-mediated increase in LY permeability but even reduced it below control level (Fig.…”

Section: Discussionmentioning

confidence: 83%

Polyamines preserve connexin 43-mediated gap junctional communication during intracellular hypercalcemia and acidosis

et al. 2017

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Changes in the regulation, formation, and gating of connexin (Cx)-based gap junction channels occur in various disorders. It has been shown that H+ and Ca2+ are involved in regulation of gap junctional communication. Ischemia-induced intracellular acidification and Ca2+ overload lead to closure of gap junctions and inhibit an exchange by ions and small molecules throughout the network of cells in the heart, brain and other tissues. In this study we examined the role of the polyamines, in the regulation of Cx43-based gap junction channels under elevated intracellular concentrations of hydrogen ([H+]i) and calcium ([Ca2+]i) ions. Experiments, performed in Novikoff and A172 human glioblastoma cells, endogenously express Cx43, revealed that polyamines prevent downregulation of Cx43-mediated gap junctional communication caused by elevated [Ca2+]i and [H+]i, accompanying ischemic and other pathological conditions. siRNA knockdown of Cx43 significantly reduce gap junctional communication, indicating that Cx43 gap junctions are the subjects of spermine regulation.

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Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy

Abstract: These results underline the complex relationship between potential tumor suppressors and treatment resistance in glioblastomas and single out GJB6/Cx30 as a potential biomarker and target for therapeutic intervention in these tumors.

Cited by 38 publications

References 77 publications

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Gap junctions and cancer: communicating for 50 years

Polyamines preserve connexin 43-mediated gap junctional communication during intracellular hypercalcemia and acidosis

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