Abstract
Glioblastoma is the most common malignant brain cancer with a dismal prognosis. The difficulty in treating glioblastoma is largely attributed to the lack of effective therapeutic targets. In our previous work, we identified casein kinase 1 ε (CK1ε, also known as CSNK1E) as a potential survival factor in glioblastoma. However, how CK1ε controls cell survival remains elusive and whether targeting CK1ε is a possible treatment for glioblastoma requires further investigation. Here we report that CK1ε was expressed at the highest level among six CK1 isoforms in glioblastoma and enriched in high-grade glioma, but not glia cells. Depletion of CK1ε remarkably inhibited the growth of glioblastoma cells and suppressed self-renewal of glioblastoma stem cells, while having limited effect on astrocytes. CK1ε deprivation activated β-catenin and induced apoptosis, which was further counteracted by knockdown of β-catenin. The CK1ε inhibitor IC261, but not PF-4800567, activated β-catenin and blocked the growth of glioblastoma cells and glioblastoma stem cells. Congruently, IC261 elicited a robust growth inhibition of human glioblastoma xenografts in mice. Together, our results demonstrate that CK1ε regulates the survival of glioblastoma cells and glioblastoma stem cells through β-catenin signaling, underscoring the importance of targeting CK1ε as an effective treatment for glioblastoma.
Highlights
Glioblastoma (GBM) is the most common form of primary malignant cancer in the central nervous system[1]
CK1ε levels were higher than other isoforms in GBM patient specimens, consistent with the results in GBM cell lines
We found that cleaved caspase 3 (c-CASP3) significantly increased, whereas levels of LC3B decreased, upon CK1ε depletion in CK1ε short hairpin RNAs (shRNAs)-responsive U87MG cells (Fig. 4D)
Summary
Glioblastoma (GBM) is the most common form of primary malignant cancer in the central nervous system[1]. The CK1ε inhibitor IC261, but not PF-4800547, activated β-catenin and mitigated the growth of GBM cells and GSCs in vitro and in vivo. ShRNAs of CK1ε or MELK significantly inhibited the viability of primary VTC-001 and VTC-002 cells (Fig. 2C), consistent with the results from GBM cell lines (Fig. 2A,B).
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