The role of autophagy in cadmium induced prostate carcinogenesis

项目摘要 已经清楚地表明，接触环境毒物镉与 与包括前列腺癌在内的多种人类疾病有关。前列腺癌是第二大病因 美国癌症死亡率。虽然已经成立了一个协会， 这种金属诱导细胞转化的机制还没有确定。一个未充分探索的过程， 可能受镉影响的是致癌性自噬，这是一个促进癌细胞存活的过程。我们 初步数据清楚地表明，长期接触镉会导致细胞转化， 这种转化通过胎盘特异性8（Plac 8）表达的变化通过自噬发生。 此外，Plac 8在人前列腺癌中观察到，但在良性前列腺增生组织中未观察到。 根据我们的初步结果，我们假设镉诱导的细胞转化是 自噬的诱导介导，Plac 8是这一过程的重要调节因子。 我们将在正常前列腺上皮（RWPE-1）中使用多种方法的组合来测试这一假设， 转化细胞和镉转化的前列腺上皮（CTPE）细胞，小鼠和人前列腺 癌该项目的目标是探索一种创新的自噬调控模型， 镉;其中短期金属暴露诱导细胞凋亡，而慢性低剂量暴露， 这更准确地代表了人类镉中毒的病因学;自噬作用致癌 从而导致转变。镉、自噬/凋亡和Plac 8之间的相互作用 表达将使用三种方法来定义：具体目标1：建立机械关系 镉暴露与前列腺上皮细胞自噬诱导之间的关系。具体目标二： 确定镉诱导Plac 8表达以调节促存活的机制 发出自噬信号具体目标-3：确定Plac 8在体内的致癌作用。成功 这些目标的完成代表了关于自噬/Plac 8在镉中的作用的第一次研究， 诱发前列腺癌它还将告知使用Plac 8作为前列腺癌的适用性 生物标志物和靶向这种蛋白质以抑制金属诱导的前列腺癌。

Project Summary It has been clearly demonstrated that exposure to the environmental toxicant cadmium is associated with a variety of human diseases including prostate cancer. Prostate cancer is the second leading cause of cancer death in United States. Although an association has been established, the mechanism by which this metal induces cellular transformation has yet to be defined. One underexplored process that may be affected by cadmium is oncogenic autophagy, a process that promotes cancer cell survival. Our preliminary data clearly shows that chronic exposure to cadmium leads to cellular transformation and that this transformation occurs via autophagy through changes in Placenta Specific 8 (Plac8) expression. Additionally, Plac8 is observed in human prostate cancer, but not in benign prostatic hyperplasia tissues. Based on our preliminary results we hypothesize that cadmium-induced cellular transformation is mediated by the induction of autophagy and that Plac8 is an essential regulator of this process. We will test this hypothesis using a combination of approaches in normal prostate epithelial (RWPE-1), transforming cells and cadmium-transformed prostate epithelial (CTPE) cells, mice and human prostate cancer. The goals of this project are to explore an innovative model for the regulation of autophagy by cadmium; where short term metal exposure induces the apoptosis, while chronic low dose exposure, which more accurately represents human etiology of cadmium toxicity; autophagy acts oncogenic leading to transformation. The interaction between cadmium, autophagy/apoptosis and Plac8 expression will be defined using three approaches: Specific Aim 1: Establish the mechanistic relationship between cadmium exposure and the induction of autophagy in prostate epithelial cells. Specific Aim 2: Determine the mechanism by-which cadmium induces Plac8 expression to regulate pro-survival signaling autophagy. Specific Aim -3: Determine the oncogenic role of Plac8 in vivo. The successful completion of these goals represents the first studies on the role of autophagy/Plac8 in cadmium- induced prostate cancer. It will also inform on the applicability of using Plac8 as a prostate cancer biomarker and of targeting this protein to inhibit metal-induced prostate cancer.