Abstract

Glioblastoma (GBM) is the most common and fatal primary brain tumor in humans, and it is essential that new and better therapies are developed to treat this disease. Previous research suggests that casein kinase 2 (CK2) may be a promising therapeutic target for GBMs. CK2 has enhanced expression or activity in numerous cancers, including GBM, and it has been demonstrated that inhibitors of CK2 regressed tumor growth in GBM xenograft mouse models. Our studies demonstrate that the CK2 subunit, CK2a, is overexpressed in and has an important role in regulating brain tumor-initiating cells (BTIC) in GBM. Initial studies showed that two GBM cell lines (U87-MG and U138) transduced with CK2a had enhanced proliferation and anchorage-independent growth. Inhibition of CKa using siRNA or small-molecule inhibitors (TBBz, CX-4945) reduced cell growth, decreased tumor size, and increased survival rates in GBM xenograft mouse models. We also verified that inhibition of CK2a decreased the activity of a well-known GBM-initiating cell regulator, ß-catenin. Loss of CK2a decreased two ß-catenin-regulated genes that are involved in GBM-initiating cell growth, OCT4 and NANOG. To determine the importance of CK2a in GBM stem cell maintenance, we reduced CK2a activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2a activity reduced the sphere-forming capacity of BTIC and decreased numerous GBM stem cell markers, including CD133, CD90, CD49f and A2B5. Our study suggests that CK2a is involved in GBM tumorigenesis by maintaining BTIC through the regulation of ß-catenin.Oncogene advance online publication, 22 September 2014; doi:10.1038/onc.2014.299.

View details for DOI 10.1038/onc.2014.299

View details for PubMedID 25241897