[en] 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-kappaB hyperactivation in malignant gliomas is at best moderate, a delayed activation of NF-kappaB may associate with the therapeutic resistance of glioma cells to CK2 inhibition.
Disciplines :
Genetics & genetic processes
Author, co-author :
Dubois, Nadège ; Centre Hospitalier Universitaire de Liège - CHU > Département ULiège > Faculté de médecine
Willems, Marie
Nguyen-Khac, Minh-Tuan
Kroonen, Jerome
Goffart, Nicolas ; Université de Liège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, et biochimie humaine
Deprez, Manuel
Bours, Vincent ; Université de Liège > Département des sciences biomédicales et précliniques > GIGA-R : Génétique humaine
Robe, Pierre ; Université de Liège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Language :
English
Title :
Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential.
Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, et al: Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA 314: 2535-2543, 2015.
Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K and Clarke MF: The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356: 217-226, 2007.
Duncan JS and Litchfield DW: Too much of a good thing: The role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Biochim Biophys Acta 1784: 33-47, 2008.
Kroonen J, Artesi M, Capraro V, Nguyen-Khac MT, Willems M, Chakravarti A, Bours V and Robe PA: Casein kinase 2 inhibition modulates the DNA damage response but fails to radiosensitize malignant glioma cells. Int J Oncol 41: 776-782, 2012.
Mandal T, Bhowmik A, Chatterjee A, Chatterjee U, Chatterjee S and Ghosh MK: Reduced phosphorylation of Stat3 at Ser-727 mediated by casein kinase 2 - protein phosphatase 2A enhances Stat3 Tyr-705 induced tumorigenic potential of glioma cells. Cell Signal 26: 1725-1734, 2014.
Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Traish AM, Mercurio F and Sonenshein GE: Roles of IKK kinases and CK2 in activation of NFκB in breast cancer. Cancer Res 61: 3810-3818, 2001.
Turowec JP, Vilk G, Gabriel M and Litchfield DW: Characterizing the convergence of protein kinase CK2 and caspase-3 reveals isoform-specific phosphorylation of caspase-3 by CK2α': Implications for pathological roles of CK2 in promoting cancer cell survival. Oncotarget 4: 560-571, 2013.
Nitta RT, Gholamin S, Feroze AH, Agarwal M, Cheshier SH, Mitra SS and Li G: Casein kinase 2α regulates glioblastoma brain tumor-initiating cell growth through the β-catenin pathway. Oncogene 34: 3688-3699, 2015.
Zheng Y, McFarland BC, Drygin D, Yu H, Bellis SL, Kim H, Bredel M and Benveniste EN: Targeting protein kinase CK2 suppresses prosurvival signaling pathways and growth of glioblastoma. Clin Cancer Res 19: 6484-6494, 2013.
Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov J P, et al; Cancer Genome Atlas Research Network: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17: 98-110, 2010.
Romieu-Mourez R, Landesman-Bollag E, Seldin DC and Sonenshein GE: Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Res 62: 6770-6778, 2002.
Guerra B, Iwabuchi K and Issinger O-G: Protein kinase CK2 is required for the recruitment of 53BP1 to sites of DNA doublestrand break induced by radiomimetic drugs. Cancer Lett 345: 115-123, 2014.
Olsen BB, Fritz G and Issinger O-G: Characterization of ATM and DNA-PK wild-type and mutant cell lines upon DSB induction in the presence and absence of CK2 inhibitors. Int J Oncol 40: 592-598, 2012.
Dixit D, Sharma V, Ghosh S, Mehta VS and Sen E: Inhibition of Casein kinase-2 induces p53-dependent cell cycle arrest and sensitizes glioblastoma cells to tumor necrosis factor (TNFα)-induced apoptosis through SIRT1 inhibition. Cell Death Dis 3: e271, 2012.
Berendsen S, Varkila M, Kroonen J, Seute T, Snijders TJ, Kauw F, Spliet WG, Willems M, Poulet C, Broekman ML, et al: Prognostic relevance of epilepsy at presentation in glioblastoma patients. Neuro Oncol: Sep 29, 2015 (Epub ahead of print]). doi:10.1093/neuonc/nov238.
Robe PA, Bentires-Alj M, Bonif M, Rogister B, Deprez M, Haddada H, Khac MT, Jolois O, Erkmen K, Merville MP, et al: In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res 10: 5595-5603, 2004.
Shen J, Channavajhala P, Seldin DC and Sonenshein GE: Phosphorylation by the protein kinase CK2 promotes calpain-mediated degradation of IkappaBalpha. J Immunol 167: 4919-4925, 2001.
Robe PA, Nguyen-Khac M-T, Lambert F, Lechanteur C, Jolois O, Ernst-Gengoux P, Rogister B and Bours V: Sulfasalazine unveils a contact-independent HSV-TK/ganciclovir gene therapy bystander effect in malignant gliomas. Int J Oncol 30: 283-290, 2007.
Bredel M, Bredel C, Juric D, Duran GE, Yu RX, Harsh GR, Vogel H, Recht LD, Scheck AC and Sikic BI: Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol 24: 274-287, 2006.
Artesi M, Kroonen J, Bredel M, Nguyen-Khac M, Deprez M, Schoysman L, Poulet C, Chakravarti A, Kim H, Scholtens D, et al: Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy. Neuro-oncol 17: 392-406. 2015.
Robe PA, Rogister B, Merville M-P and Bours V: Growth regulation of astrocytes and C6 cells by TGFbeta1: Correlation with gap junctions. Neuroreport 11: 2837-2841, 2000.
Goffart N, Kroonen J and Rogister B: Glioblastoma-initiating cells: Relationship with neural stem cells and the micro-environment. Cancers (Basel) 5: 1049-1071, 2013.
Kore RA and Abraham EC: Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells. Biochem Biophys Res Commun 453: 326-331, 2014.
Bredel M, Scholtens DM, Yadav AK, Alvarez AA, Renfrow JJ, Chandler JP, Yu IL, Carro MS, Dai F, Tagge MJ, et al: NFKBIA deletion in glioblastomas. N Engl J Med 364: 627-637, 2011.
Yu M, Yeh J and van Waes. C: Protein kinase casein kinase 2 mediates inhibitor-kappaB kinase and aberrant nuclear factor-kappaB activation by serum factor(s) in head and neck squamous carcinoma cells. Cancer Res 66: 6722-6731, 2006.
Guo S, Demicco EG, Romieu-Mourez R, Landesman-Bollag E, Seldin DC and Sonenshein GE: Inducible IκB kinase/IκB kinase ϵ expression is induced by CK2 and promotes aberrant nuclear factor-κB activation in breast cancer cells. Cancer Res 65: 11375-11383, 2005.
