Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institute of Medical Science, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Cell Death Dis. 2011 Dec 8;2(12):e241. doi: 10.1038/cddis.2011.126.
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.
提高胶质母细胞瘤细胞对辐射的敏感性是提高胶质母细胞瘤（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（PP6））是否是 GBM 放射增敏治疗的分子靶点。本研究使用了 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 PP6 催化亚基（PP6c）的蛋白水平上调。GBM 细胞的体外存活分数和患者的生存时间与 PP6c 表达高度相关或呈负相关（分别为 R(2)=0.755 和-0.707）。我们还发现，在三种不同的 GBM 细胞系中，PP6c 的 siRNA 敲低降低了 DNA 依赖性蛋白激酶（DNA-PK）的活性，从而增加了它们对辐射的敏感性。在原位小鼠模型中，PP6c 在 GBM U87 细胞中的过表达减弱了放射治疗的效果，与对照组小鼠相比，降低了小鼠的生存时间，而 PP6c 的敲低则提高了放射治疗的效果，增加了小鼠的生存时间。这些发现表明 PP6 调节 GBM 细胞对辐射的敏感性，并表明破坏或抑制 PP6 与 DNA-PK 结合的小分子可能是 GBM 的一种潜在放射增敏剂。
