Casein kinase 2α regulates glioblastoma brain tumor-initiating cell growth through the β-catenin pathway.
Casein kinase 2α regulates glioblastoma brain tumor-initiating cell growth through the β-catenin pathway.
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胶质母细胞瘤（GBM）是人类最常见和最致命的原发性脑肿瘤，开发新的更好的治疗方法来治疗这种疾病至关重要。以往的研究表明，酪蛋白激酶2（CK 2），可能是一个有前途的治疗GBM的目标。CK 2在包括GBM在内的许多癌症中具有增强的表达或活性，并且已经证明CK 2的抑制剂使GBM异种移植小鼠模型中的肿瘤生长消退。我们的研究表明，CK 2亚基，CK 2 α，在GBM中过表达，并在调节脑肿瘤起始细胞（BTIC）中起重要作用。初步研究表明，CK 2 α转导的两种GBM细胞系（U87-MG和U138）具有较强的增殖能力和非贴壁依赖性生长。在GBM异种移植小鼠模型中，使用siRNA或小分子抑制剂（TBBz，CX-4945）抑制CK 2 α可减少细胞生长，减小肿瘤大小，并增加存活率。我们还证实了CK 2 α的抑制降低了众所周知的GBM起始细胞调节因子β-连环蛋白的活性。CK 2 α的缺失降低了参与GBM启动细胞生长的两个β-连环蛋白调节基因OCT 4和NANOG。为了确定CK 2 α在GBM干细胞维持中的重要性，我们降低了原代GBM样品和来自GBM患者的肿瘤球中的CK 2 α活性。我们发现，CK 2 α活性的丧失降低了BTIC的球体形成能力，并降低了许多GBM干细胞标志物，包括CD 133、CD 90、CD 49 f和A2 B5。我们的研究表明，CK 2 α通过调节β-catenin维持BTIC参与GBM肿瘤的发生。
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, CK2α, is overexpressed in and plays 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 CK2α had enhanced proliferation and anchorage-independent growth. Inhibition of CK2α using siRNA or small molecule inhibitors (TBBz, CX-4945) reduced cell growth and decreased tumor size and increased the survival rate in GBM xenograft mouse models. We also verified that inhibition of CK2α decreased the activity of a well-known GBM initiating cell regulator, β-catenin. Loss of CK2α decreased two β-catenin-regulated genes that are involved in GBM initiating cell growth, OCT4 and NANOG. To determine the importance of CK2α in GBM stem cell maintenance, we reduced CK2α activity in primary GBM samples and tumor spheres derived from GBM patients. We discovered that loss of CK2α 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 CK2α is involved in GBM tumorigenesis by maintaining BTIC through the regulation of β-catenin.
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