Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma.
Serine/threonine protein phosphatase 6 modulates the radiation sensitivity of glioblastoma.
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丝氨酸/苏氨酸蛋白磷酸酶6调节胶质母细胞瘤的放射敏感性
DOI：
10.1038/cddis.2011.126
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发表时间：
2011-12-08
影响因子：
9
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中科院分区：
文献类型：
--
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增加胶质母细胞瘤细胞对放射的敏感性是提高多形性胶质母细胞瘤（GBM）患者生存率的一种有前途的方法。本研究旨在确定丝氨酸/苏氨酸磷酸酶（蛋白磷酸酶6（PP 6））是否是GBM放射增敏治疗的分子靶点。本研究使用GBM原位异种移植小鼠模型。我们的数据表明，与周围组织或对照组织相比，约50%的患者的GBM组织中PP 6催化亚基（PP 6c）的蛋白水平上调。GBM细胞的体外存活分数和患者存活时间与PP 6c表达高度相关或负相关（R2分别为0.755和-0.707）。我们还发现，PP 6c的siRNA敲低降低了三种不同GBM细胞系中的DNA依赖性蛋白激酶（DNA-PK）活性，增加了它们对辐射的敏感性。在原位小鼠模型中，PP 6c在GBM U87细胞中的过表达减弱了放射治疗的效果，与对照组相比，小鼠的存活时间缩短;而PP 6c敲低则增强了放射治疗的效果，延长了小鼠的存活时间。这些发现表明，PP 6调节GBM细胞对辐射的敏感性，并表明破坏或抑制PP 6与DNA-PK的结合的小分子是GBM的潜在辐射增敏剂。
Increasing the sensitivity of glioblastoma cells to radiation is a promising approach to improve survival in patients with glioblastoma multiforme (GBM). This study aims to determine if serine/threonine phosphatase (protein phosphatase 6 (PP6)) is a molecular target for GBM radiosensitization treatment. The GBM orthotopic xenograft mice model was used in this study. Our data demonstrated that the protein level of PP6 catalytic subunit (PP6c) was upregulated in the GBM tissue from about 50% patients compared with the surrounding tissue or control tissue. Both the in vitro survival fraction of GBM cells and the patient survival time were highly correlated or inversely correlated with PP6c expression (R 2= 0.755 and− 0.707, respectively). We also found that siRNA knockdown of PP6c reduced DNA-dependent protein kinase (DNA-PK) activity in three different GBM cell lines, increasing their sensitivity to radiation. In the orthotopic mice model, the overexpression of PP6c in GBM U87 cells attenuated the effect of radiation treatment, and reduced the survival time of mice compared with the control mice, while the PP6c knocking-down improved the effect of radiation treatment, and increased the survival time of mice. These findings demonstrate that PP6 regulates the sensitivity of GBM cells to radiation, and suggest small molecules disrupting or inhibiting PP6 association with DNA-PK is a potential radiosensitizer for GBM.
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