Abstract
Objective Casein kinase 2 interacting protein-1 (CKIP-1) has exhibited multiple functions in regulating cell proliferation, apoptosis, differentiation, and cytoskeleton. CKIP-1 also plays an important role as a critical regulator in tumorigenesis. The aim of this study is to further examine the function of CKIP-1 in glioma cells. Methods The expression level of CKIP-1 protein was determined in gliomas tissues and cell lines by immunohistochemistry stain and western blotting while the association of CKIP-1 expression with prognosis was analyzed by Kaplan-Meier method and compared by log-rank test. CKIP-1 was overexpressed or silenced in gliomas cell lines. CCK-8, colony formation assay, and BrdU incorporation assay were used to determine cell proliferation and DNA synthesis. Cell cycle and apoptosis rate were determined with fluorescence-activated cell sorting (FACS) method. Then, expression of key members in AKT/GSK3β/β-catenin pathway was detected by western blot analysis. Results In the present study, we reported new evidence that CKIP-1 was reversely associated with the proliferation of glioma cells and survival in glioma patients. Additionally, the overexpressed CKIP-1 significantly inhibited glioma cell proliferation. Further experiments revealed that CKIP-1 functioned through its antiproliferative and proapoptotic activity in glioma cells. Importantly, mechanistic investigations suggested that CKIP-1 sharply suppressed the activity of AKT by inhibiting the phosphorylation, markedly downregulated the phosphorylated GSK3β at Ser9, and promoted β-catenin degradation. Conclusions Overall, our results provided new insights into the clinical significance and molecular mechanism of CKIP-1 in glioma, which indicated CKIP1 might function as a therapeutic target for clinical treatment of glioma.
Highlights
In the central nervous system, gliomas are the most common type of aggressive primary solid tumor, accounting for ∼80% of primary malignant brain tumors
We found Casein kinase interacting protein-1 (CKIP-1) staining clearly was localized to the cytoplasm and nuclei in nontumor brain tissue (Figure 1(a)) and generally higher than glioma tissue
CKIP-1 depletion (U87-RNAi) resulted in an accumulation in S phase in greater numbers but reduced that in G0/G1 phase than U87-Ctrl cells (all p < 0.01; Figure 3(b), right). These results demonstrated that CKIP-1 arrested glioma cells at the G0/G1 phase which control that cells do not exit from G1 phase and enter into S phase of the cell cycle, while depletion of CKIP-1 reversed the accumulation in the G0 /G1 phase and allowed the glioma cells to enter into S phase, suggesting that CKIP-1 may function through its antiproliferative activity in glioma cells
Summary
In the central nervous system, gliomas are the most common type of aggressive primary solid tumor, accounting for ∼80% of primary malignant brain tumors. Malignant glioma is characterized by invasion into surrounding brain tissues, rapid proliferation, and aberrant angiogenesis [2]. These biological characteristics lead to unclear boundaries between tumors and surrounding brain tissues and the glioma cells usually spread deep into the brain which pose a great challenge to surgeons. Multiple therapies include maximum safe resection, followed by chemotherapy, radiation, and immunotherapy, the outcome of patients diagnosed with high-grade glioma remains unsatisfied, with median survival of less than 15 months [3, 4]. It is vital to investigate the specific molecular mechanism that regulate the progression of glioma and identify the novel molecular therapeutic targets to aid in development of glioma therapies
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