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Radiation-induced erbB-dependent activation of Akt-DNA-PKcs signaling and its role in radioresistance of solid tumors

辐射诱导的 erbB 依赖性 Akt-DNA-PKcs 信号激活及其在实体瘤放射抗性中的作用

基本信息

批准号：
251207142
负责人：
Professor Dr. H. Peter Rodemann
金额：
--
依托单位：
Universitätsklinik für Radioonkologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/251207142?language=en
关键词：
Radiation induced erbB dependent activation

项目摘要

Previous research performed within the first funding period of the DFG-SFB 773 "Understanding and Overcoming Therapy Resistance of Solid Tumors" revealed that the erbB-receptor-dependent PI3K/Akt cascade is an important regulator of repair of radiation-induced DNA-double strand breaks (DNA-DSB). Thus, DNA repair signaling through this cascade seems to be a prominent feature of radioresistance of human solid tumors presenting overexpressed or mutated erbB receptors. In this context a direct protein-protein interaction between Akt1 and DNA-PKcs, which is the key enzyme of the Non-Homologous End-Joining repair mechanism (NHEJ) was described for the first time. Interaction of Akt1 and DNA-PKcs seems to be necessary for initiation, progression and termination of the NHEJ repair process. Moreover, recent data from other laboratories indicate a PI3K-independent activity of Akt in the NHEJ and potentially the homologous recombination (HR) repair mechanisms as well. Thus, the goal of the project is to identify the specific mechanisms by which Akt stimulates DNA-DSB repair in a PI3K-dependent and -independent manner. To elucidate the detailed mechanisms, the project will focus on the specific role of Akt isoforms activated via erbB-PI3K signaling in the cytoplasm and translocated to the nucleus as well as on the direct nuclear activation of Akt via MRE11 and ATM signaling. In addition to these basic research aspects addressed in vitro, studies on irradiated human tumor xenografts will exploit the efficacy of Akt and ATM antagonists on DNA-DSB repair in vivo. Understanding the specific role of PI3K-dependent and -independent Akt signaling in the regulation of the repair of radiotherapy-induced DNA-DSB may open novel targeting strategies to overcome radioresistance of human solid tumors.

先前在DFG-SFB 773项目“理解和克服实体肿瘤的治疗抗性”的第一个资助期内进行的研究表明，erbb受体依赖的PI3K/Akt级联是辐射诱导的dna -双链断裂（DNA-DSB）修复的重要调节因子。因此，通过这种级联的DNA修复信号似乎是呈现过表达或突变的erbB受体的人类实体肿瘤放射耐药的一个突出特征。在这种情况下，Akt1与DNA-PKcs之间的直接蛋白-蛋白相互作用首次被描述，而DNA-PKcs是非同源末端连接修复机制（NHEJ）的关键酶。Akt1和DNA-PKcs的相互作用似乎是NHEJ修复过程的启动、进展和终止所必需的。此外，最近来自其他实验室的数据表明，Akt在NHEJ中具有不依赖pi3k的活性，并且可能具有同源重组（HR）修复机制。因此，该项目的目标是确定Akt以pi3k依赖和不依赖的方式刺激DNA-DSB修复的具体机制。为了阐明其具体机制，该项目将重点研究通过erbB-PI3K信号激活的Akt同工异构体在细胞质中转运到细胞核中的具体作用，以及通过MRE11和ATM信号直接激活Akt的核。除了在体外进行的这些基础研究外，对辐照的人类肿瘤异种移植物的研究将利用Akt和ATM拮抗剂对体内DNA-DSB修复的作用。了解pi3k依赖性和非依赖性Akt信号在放疗诱导的DNA-DSB修复调控中的具体作用，可能为克服人类实体肿瘤的放射耐药开辟新的靶向策略。