DDR signaling诱导Apoptin促肿瘤放射增敏治疗的研究

The strategy of Radiotherapy sensitization is removal of radio-induced G2 arrest. The viral protein Apoptin can induce G2 / M arrest, but it can also improve the sensitization of tumor radiotherapy, it is important to explore the mechanism. DDR signaling, triggered by DNA damage, is an important procedure for the maintenance of chromosomal stability involving restoration of the the DNA construction, activation of cell cycle checkpoint, transcriptional response, andinduction of apoptosis. Kucharski showed that DDR signaling, which could be activated by DNA damage induced by chemical reagents, can enhance the nuclear localization of Apoptin which contributed to an induction of apoptosis in tumor cells. In contrast, Activated Apoptin also inhibit DNArepairation. It's an assumption that: DDR signaling activateded by radiotherapy may activate Apoptin, promoting apoptosis of tumor cells, activation of Apoptin may inhibit tumor cell which sensitive DDR signaling damage repair. This study aims to investigate the relevance between Apoptin and DDR signaling due to radiation, evaluate the effects of short peptides Ap (100-109) and Ap ( 82-121 ) sensitization of radiotherapy. The results could providean oretical basis .for the development of new tumor radiotherapy.

肿瘤放疗增敏的策略是去除放射线引起的肿瘤细胞G2期阻滞。Apoptin能引起肿瘤细胞G2/M期阻滞，但其也能促肿瘤放疗增敏，故探讨其机制尤为重要。DNA损伤引起DDR signaling反应，通过 DNA修复、激活细胞周期关卡、调节转录水平、启动凋亡程序维持染色体稳定。Kucharski等研究提示化学损伤引起DDR signaling诱导Apoptin核定位，激活促凋亡活性；活化的Apoptin反而抑制DNA损伤修复。由此我们推测：射线照射肿瘤细胞后DDR signaling可能诱导Apoptin核定位，促进肿瘤细胞凋亡，活化的Apoptin反而可能抑制DDR signaling敏感肿瘤细胞损伤修复？！本研究拟探讨射线照射后DDR signaling与Apoptin关系；并评价Ap(100-109)，Ap（82-121）短肽放疗增敏效果。此研究将为开发新的肿瘤放疗增敏剂提供理论基础。

肿瘤放疗增敏的策略是去除放射线引起的肿瘤细胞G2 期阻滞。Apoptin 能引起肿瘤细胞G2/M 期阻滞，但其也能促肿瘤放疗增敏，故探讨其机制尤为重要。DNA 损伤引起DDR signaling 反应，通过DNA 修复、激活细胞周期关卡、调节转录水平、启动凋亡程序维持染色体稳定。化学损伤引起DDR signaling 诱导Apoptin 核定位，激活促凋亡活性；活化的Apoptin 反而抑制DNA 损伤修复。由此我们研究发现：射线照射肿瘤细胞后DDR signaling 可能诱导Apoptin 核定位，促进肿瘤细胞凋亡，活化的Apoptin 反而可能抑制DDR signaling 敏感肿瘤细胞损伤修复。同时，我们发现发现Ku80可能是Apoptin抑制NHEJ的重要靶点，抑制Ku80在DNA双链损伤位点的聚集是Apoptin放射增敏的重要分子机制。