Casein Kinase 2: A Novel Player in Glioblastoma Therapy and Cancer Stem Cells

Abstract

Casein kinase 2 (CK2) is an oncogenic protein kinase which contributes to tumor development, proliferation, and suppression of apoptosis in multiple cancer types. The mechanism by which CK2 expression and activity leads to tumorigenesis in glioblastoma (GBM), a stage IV primary brain tumor, is being studied. Recent studies demonstrate that CK2 plays an important role in GBM formation and growth through the inhibition of tumor suppressors and activation of oncogenes. In addition, intriguing new reports indicate that CK2 may regulate GBM formation in a novel manner; CK2 may play a critical role in cancer stem cell (CSC) maintenance. Since glial CSCs have the ability to self-renew and initiate tumor growth, new treatments which target these CSCs are needed to treat this fatal disease. Inhibition of CK2 is potentially a novel method to inhibit GBM growth and reoccurrence by targeting the glial CSCs. A new, orally available, selective CK2 inhibitor, CX-4945 has had promising results when tested in cancer cell lines, in vivo xenograft models, and human clinical trials. The development of CK2 targeted inhibitors, starting with CX-4945, may lead to a new class of more effective cancer therapies.

Phenotype stability under dynamic brain-tumor environment stimuli maps glioblastoma progression in patients

“…We explored the impact of several representative examples of experimentally and clinically relevant drugs for GBM on the predicted cell phenotype dynamics. These included CK2 ( 26 ), epidermal growth factor receptor (EGFR) ( 27 ), MAPK kinase (MEK) ( 28 ), SRC ( 29 ), TGFBR ( 30 ), the combination of MEK and TGFBR ( 28 , 30 ), and the combination of RAF and CK2 ( 31 , 32 ). Details of the targeted network analyses and results are listed in file S2 and tables S2 and S3.…”

Calpastatin phosphorylation regulates radiation-induced calpain activity in glioblastoma

“…In order to identify the kinase that phosphorylates calpastatin specifically at serines 633 and 351, we utilized two sequence-based kinase prediction tools (KinasePhos [ 31 ] and NetPhos 3.1 [ 32 ]). Casein kinase 2 (CK2) was predicted by both tools to phosphorylate calpastatin serines 633 and 351, and has previously been reported to play a role in GSC maintenance [ 33 ]. To test the hypothesis that CK2 phosphorylates calpastatin at Ser-633, we treated cells with the CK2 inhibitor CX-4945 and calyculin A.…”

“…Casein kinase 2 is elevated in GBM tumors and 33% of GBMs were found to have gene dosage gains in CSNK2A1 , the catalytic subunit of CK2 [ 38 – 39 ]. CK2 has been implicated in GSC growth and maintenance [ 33 ], which may explain why calpastatin phosphorylation was observed in GSCs post-radiation, but not U87. CK2 also has a role in the early radiation response and regulates proteins involved in DNA double-strand break repair [ 40 – 41 ], which is consistent with our model that CK2 phosphorylates calpastatin soon after radiation treatment.…”