The role of autophagy in cadmium induced prostate carcinogenesis

项目摘要 已经清楚地证明，接触环境毒物镉与 患有包括前列腺癌在内的多种人类疾病。前列腺癌是第二大诱因。 在美国癌症死亡人数最多。虽然已经建立了关联，但该机制由 这种金属诱导细胞转化的是什么还没有确定。一个未被充分探索的过程 可能受镉影响的是致癌的自噬，这是一个促进癌细胞存活的过程。我们的 初步数据清楚地表明，慢性接触镉会导致细胞转化和 这种转变是通过胎盘特异性8(PLAC8)表达的变化而通过自噬发生的。 此外，PLAC8在人前列腺癌中观察到，但在良性前列腺增生症组织中没有观察到。 根据我们的初步结果，我们假设镉诱导的细胞转化是 通过诱导自噬，PLAC8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验证这一假设， 转化细胞和镉转化的前列腺上皮细胞、小鼠和人前列腺 癌症。这个项目的目标是探索一种通过以下方式调控自噬的创新模式 镉；短期金属暴露诱导细胞凋亡，而长期低剂量暴露， 更准确地代表了镉中毒的人类病因学；自噬起致癌作用 导致了转变。镉、自噬/细胞凋亡与PLAC8的相互作用 表达将使用三种方法来定义：具体目标1：建立机制关系 镉暴露和诱导前列腺上皮细胞自噬之间的关系。具体目标2： 镉诱导PLAC8表达调控促生存机制的研究 发出自噬信号。特异目的-3：确定PLAC8在体内的致癌作用。成功者 这些目标的完成代表着对自噬/PLAC8在镉中的作用的第一次研究。 诱发前列腺癌。它还将介绍使用PLAC8作为前列腺癌的适用性 生物标志物和靶向该蛋白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.