Radiosensitization via Targeting Cell Death

描述（由申请人提供）：细胞存活或死亡的命运受到严格调控。细胞凋亡是细胞死亡的主要机制之一，在许多癌症中是有缺陷的。凋亡发生在照射的实体瘤内的小部分细胞中。自噬是一种利用溶酶体/空泡进行细胞降解的高度保守的自我消除机制，是细胞凋亡被阻断时的备用细胞死亡途径。我们的初步数据支持这样的假设，即自噬是一个重要的替代性细胞死亡机制暴露于电离辐射的肿瘤细胞时，细胞凋亡途径被阻断。在不存在促凋亡蛋白巴克/Bax或半胱天冬酶3/7的情况下，我们发现自噬被上调并且发生在超过50%的辐射细胞中。因此，我们发现上调自噬赋予癌细胞增加的辐射敏感性。这一假说的核心是这样一个概念，即巴克/Bax或半胱天冬酶3/7在辐射诱导的应激后负调节自噬，并且自噬在缺乏这些促凋亡蛋白的细胞中增强。我们认为，通过1）mTOR抑制剂或自噬蛋白过表达直接激活自噬信号传导;或2）抑制巴克/Bax或半胱天冬酶3/7诱导自噬，将增强癌症模型中放射的生物学效应。提出了三个具体目标来检验这一假设。具体目标1将确定巴克/Bax或半胱天冬酶3/7调节辐射诱导的自噬的机制。特异性目标2将确定巴克/Bax或半胱天冬酶3/7的抑制、自噬途径的诱导和增强的放射增敏是否是癌细胞中的整体应答。特异性目标3将确定通过抑制mTOR或过表达自噬蛋白诱导自噬信号传导是否增强辐射应答。这项研究旨在了解辐射诱导的应激过程中细胞凋亡和自噬之间的分子相互作用，并确定增强癌症模型放射治疗的新靶点。这项研究的意义在于扩大我们对复杂的分子信号传导的理解，这决定了辐射细胞的命运。这些知识将被探索，以提高癌症患者使用的传统放射治疗的疗效。

DESCRIPTION (provided by applicant): The fate of cell survival or death is a tightly regulated. Apoptosis, one of the major cell death mechanisms, is defective in many cancers. Apoptosis occurs in small fraction of cells within the irradiated solid tumors. Autophagy, a highly conserved self-elimination mechanism that utilizes lysosome/vacuoles for cellular degradation is a backup cell death pathway when apoptosis is blocked. Our preliminary data support the hypothesis that autophagy is an important alternative cell death mechanism in tumor cells exposed to ionizing radiation when the apoptotic pathway is blocked. In the absence of pro-apoptotic proteins, Bak/Bax or caspase 3/7, we found that autophagy is upregulated and occurred in over 50% of irradiated cells. As a consequence, we found that up-regulation autophagy confers increased radiation sensitivity of cancer cells. Central to this hypothesis is the concept that Bak/Bax or caspase 3/7 negatively regulate autophagy, upon radiation-induced stress and that autophagy is enhanced in cells lacking these pro-apoptotic proteins. We believe that induction of autophagy through 1) direct activation of autophagic signaling by mTOR inhibitors or overexpression of autophagic proteins; or 2) inhibition of Bak/Bax or caspase 3/7, will enhance the biological effects of radiation in cancer models. Three specific aims are proposed to test this hypothesis. Specific Aim 1 will identify mechanisms by which Bak/Bax or caspase 3/7 regulate radiation-induced autophagy. Specific Aim 2 will determine whether inhibition of Bak/Bax or caspase 3/7, induction of the autophagic pathway, and enhanced radiosensitization is a global response in cancer cells. Specific Aim 3 will determine whether induction of autophagic signaling by inhibition of mTOR or over expression of autophagic proteins enhances radiation response. The proposed study is to understand the molecular interaction between apoptosis and autophagy during radiation-induced stress and to identify novel targets for enhancing radiotherapy in cancer models. The significance of this study is to expand our understanding of the complex molecular signaling, which determines the fate of irradiated cells. This knowledge will be explored to improve the efficacy of conventional radiotherapy that is being used for cancer patients.