Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Since surviving patients experience severe neurocognitive disabilities, better and more effective treatments are needed to enhance their quality of life. Casein kinase 2 (CK2) is known to regulate cell growth and survival in multiple cancers; however, the role of CK2 in MB is currently being studied. In this study, we verified the importance of CK2 in MB tumorigenesis and discovered that inhibition of CK2 using the small molecule inhibitor, CX-4945, can sensitize MB cells to a well-known and tolerated chemotherapeutic, temozolomide (TMZ). To study the role of CK2 in MB we modulated CK2 expression in multiple MB cells. Exogenous expression of CK2 enhanced cell growth and tumor growth in mice, while depletion or inhibition of CK2 expression decreased MB tumorigenesis. Treatment with CX-4945 reduced MB growth and increased apoptosis. We conducted a high-throughput screen where 4000 small molecule compounds were analyzed to identify compounds that increased the anti-tumorigenic properties of CX-4945. TMZ was found to work synergistically with CX-4945 to decrease cell survival and increase apoptosis in MB cells. O-6-methylguanine-DNA methyltransferase (MGMT) activity is directly correlated to TMZ sensitivity. We found that loss of CK2 activity reduced β-catenin expression, a known MGMT regulator, which in turn led to a decrease in MGMT expression and an increased sensitivity to TMZ. Our findings show that CK2 is important for MB maintenance and that treatment with CX-4945 can sensitize MB cells to TMZ treatment.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for ~20% of all pediatric central nervous system (CNS) tumors [1]
We analyzed a cohort of 763 primary MB samples from the Medulloblastoma Advanced Genomics International Consortium and determined that MB patients with high-mRNA expression of CK2α or CK2β have a significantly worse prognosis compared to their lowexpressing counterparts (p < 0.05) (Fig. 1a) [9]
Using one-way analysis of variance (ANOVA) we determined that CK2α expression was significantly elevated in all three datasets compared to the normal brain tissue array (p < 0.05), while there was no increase in CK2β expression in any of the three MB datasets (Fig. 1b)
Summary
Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for ~20% of all pediatric central nervous system (CNS) tumors [1]. Current multimodal treatment has led to a 70–90% 5-year overall survival rate [2]. The 5-year disease-free survival rate remains at 30%, and the prognosis for patients with tumor dissemination and recurrent MB remains poor [3]. The majority of survivors exhibit long-term neurocognitive and neuroendocrine complications as a result of the cytotoxic drugs and high-dose radiation. More effective and less toxic treatments are necessary in order to raise the quality of life for these young patients
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