| Autor: |
Nitta RT; Department of Neurosurgery, Stanford University, Stanford, CA, USA. rnitta@stanford.edu., Bolin S; Department of Neurosurgery, Stanford University, Stanford, CA, USA., Luo E; Department of Neurosurgery, Stanford University, Stanford, CA, USA., Solow-Codero DE; High-Throughput Bioscience Center, Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA., Samghabadi P; Department of Neuropathology, Stanford University, Stanford, CA, USA., Purzner T; Department of Developmental Biology, Stanford University, Stanford, CA, USA.; Division of Neurosurgery, University of Toronto, Toronto, ON, Canada., Aujla PS; Department of Neurosurgery, Stanford University, Stanford, CA, USA., Nwagbo G; Department of Neurosurgery, Stanford University, Stanford, CA, USA., Cho YJ; Department of Pediatrics, Papé Family Pediatric Research Institute, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA., Li G; Department of Neurosurgery, Stanford University, Stanford, CA, USA. |
| Abstrakt: |
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. |
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