The role of autophagy in cadmium induced prostate carcinogenesis

自噬在镉诱导前列腺癌发生中的作用

• 批准号: 10402525
• 负责人: Murali Ankem
• 金额: $ 38.2万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-20 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402525
• 关键词: Acute; Affect; Apoptosis; Autophagocytosis; Benign Prostatic Hypertrophy; Cadmium; Cancer Etiology; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Chronic; Data; Dose; Epithelial; Epithelial Cells; Etiology; Exposure to; Genes; Gleason Grade for Prostate Cancer; Goals; Human; Human Pathology; Hypoxia; Malignant neoplasm of prostate; Mediating; Metal exposure; Metals; Modeling; Molecular; Mus; Nude Mice; Oncogenic; Organelles; Oxidative Stress; Patients; Pharmacology; Placenta; Population; Prevention; Process; Prostate; Prostatic Neoplasms; Proteins; Regulation; Research; Resistance; Role; Screening for Prostate Cancer; Serum; Signal Transduction; Site-Directed Mutagenesis; Specimen; Starvation; Stress; System; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Translational Research; Tumor Tissue; United States; Urine; Xenograft Model; base; cancer biomarkers; cancer cell; carcinogenesis; cell transformation; early detection biomarkers; environmental chemical; genetic activator; genetic inhibitor; human disease; in vivo; innovation; lysosomal proteins; malignant phenotype; metaplastic cell transformation; mouse model; novel; overexpression; prostate carcinogenesis; transcription factor; tumor growth; tumor xenograft; virtual

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.

项目概要 已经清楚地证明，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。前列腺癌是第二大原因 美国癌症死亡人数。虽然成立了协会，但机制 这种金属诱导细胞转化的方式尚未确定。一种尚未充分探索的过程 镉可能会影响致癌自噬，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，长期接触镉会导致细胞转化和 这种转化是通过胎盘特异性 8 (Plac8) 表达的变化通过自噬发生的。 此外，Plac8 在人类前列腺癌中观察到，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 通过诱导自噬介导，Plac8 是该过程的重要调节因子。 我们将在正常前列腺上皮 (RWPE-1) 中结合使用多种方法来检验这一假设， 转化细胞和镉转化前列腺上皮 (CTPE) 细胞、小鼠和人前列腺 癌症。该项目的目标是探索一种自噬调控的创新模型 镉;其中短期金属暴露会诱导细胞凋亡，而长期低剂量暴露， 它更准确地代表了镉毒性的人类病因学；自噬具有致癌作用 导致转型。镉、自噬/凋亡和 Plac8 之间的相互作用 表达式将使用三种方法定义： 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2： 确定镉诱导 Plac8 表达以调节促生存的机制 信号自噬。具体目标 -3：确定 Plac8 在体内的致癌作用。成功者 这些目标的完成代表了关于自噬/Plac8 在镉- 诱发前列腺癌。它还将告知使用 Plac8 作为前列腺癌的适用性 生物标志物以及靶向该蛋白质来抑制金属诱导的前列腺癌。