IR signaling through PP6, a potential molecular target for radiosensitization

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种几乎一致的致命性脑癌。目前GBM的治疗方法是放疗加口服化疗。接受化疗和放疗的GBM患者的预期寿命只有14个月。这些统计数据表明，需要更好的治疗方法来提高放射治疗GBM的有效性。辐射会导致DNA损伤，从而激活被认为可以提高细胞修复DNA损伤能力的信号通路。辐射引发的损伤感应途径在很大程度上依赖于蛋白质磷酸化（向蛋白质添加磷酸基团）。蛋白质磷酸化反映了两组相反的酶之间的平衡：向蛋白质添加磷酸基团的激酶和从蛋白质中去除磷酸基团的磷酸酶。阻断激酶的药物已经成功地用于提高放射治疗的临床效果。例如，晚期头颈部癌症除了使用阻断激酶的药物外，还使用放射治疗。然而，在这个时候，蛋白磷酸酶很少受到关注，但有可能使辐射更有效。我们发现了一种新发现的蛋白磷酸酶，称为磷酸酶-6（PP 6），它在调节一种称为DNA-PK的关键DNA修复蛋白中起着关键作用。PP 6的耗尽显著地使胶质母细胞瘤细胞对辐射敏感。我们的长期目标是通过使用阻断PP 6激活DNA-PK能力的药物，使胶质母细胞瘤细胞对辐射更敏感。然而，在使用这些药物之前，有必要确定PP 6在辐射后调节DNA-PK的分子机制。

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is an almost uniformly fatal brain cancer. The current treatment for GBM is radiation with oral chemotherapy. GBM patients treated with chemotherapy and radiation have life expectancies of only 14 months. These statistics make it obvious that better treatment approaches are needed to improve the effectiveness of radiation for GBM. Radiation causes DNA damage which activates signaling pathways that are thought to improve the ability of cells to repair DNA damage. The damage sensing pathways that are triggered by radiation, for the most part, are dependent on protein phosphorylation (adding a phosphate group to proteins). Protein phosphorylation reflects the balance between two opposing sets of enzymes: kinases that add a phosphate group to proteins and phosphatases that remove a phosphate group from proteins. Drugs that block kinases have already been successfully used to improve the clinical effectiveness of radiation therapy. For example, advanced-stage head and neck cancers are treated with radiation in addition to a drug that blocks kinases. At this time, however, protein phosphatases have received little attention but have the potential to make radiation more effective. We have discovered a specific role for a newly discovered protein phosphatase called phosphatase-6 (PP6) which plays a critical role in regulating a key DNA repair protein called DNA-PK. Depletion of PP6 dramatically sensitizes glioblastoma cells to radiation. Our long term goal is to make glioblastoma cells more sensitive to radiation through the use of drugs that block PP6's ability to activate DNA-PK. However, before such drugs can be used, it is necessary to define the molecular mechanisms by which PP6 regulates DNA-PK following radiation.