Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma
| Autor: | Xiao-Nan Li, Margaret T. Fuller, Joshua E. Elias, Taylor Buckstaff, Ryan T. Nitta, Gordon Li, Giorgio Cozza, Yoon Jae Cho, Michael D. Taylor, Lorenzo A. Pinna, Lauren Ellis, Marc Langan, Sharareh Gholamin, Lin Qi, Johanna Theruvath, Nicholas R. Conley, Vijay Ramaswamy, Robert J. Wechsler-Reya, Ulrike M. Litzenburger, Xuecai Ge, John L. Sanders, James Purzner, Teresa Purzner, Tom A. Hartl, Matthew P. Scott, Jessica M. Rusert, Sara Bolin |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Proteomics
0301 basic medicine animal structures Pyridines Mice Nude Kaplan-Meier Estimate Mice SCID Biology Biochemistry Article Mice 03 medical and health sciences Mice Inbred NOD Cell Line Tumor GLI2 medicine Animals Humans Anilides Hedgehog Proteins Naphthyridines Sonic hedgehog Casein Kinase II Cerebellar Neoplasms Transcription factor Molecular Biology Mice Knockout Medulloblastoma Phosphoproteomics Neoplasms Experimental Cell Biology Phosphoproteins medicine.disease Xenograft Model Antitumor Assays Hedgehog signaling pathway Gene Expression Regulation Neoplastic 030104 developmental biology embryonic structures NIH 3T3 Cells Cancer research biology.protein Phenazines Phosphorylation Signal transduction Signal Transduction |
| Popis: | A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology. |
| Databáze: | OpenAIRE |
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