Mechanism of cancer progression in prostate cancer cells

前列腺癌细胞的癌症进展机制

基本信息

批准号：
10360599
负责人：
xiaoping Yi
金额：
$ 21万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360599
关键词：
1,3-Butadiene 3-Dimensional Age Antibodies Antineoplastic Agents Apoptosis Apoptotic Automobile Exhaust Binding Biological Butadiene CRISPR/Cas technology Cell Cycle Cell Cycle Arrest Cell model Cell physiology Cells Cessation of life Characteristics Chemicals Chemoresistance DNA DU145 Data Diet Drug resistance E-Cadherin Epithelial Ethnic Origin Exposure to FRAP1 gene Gene Mutation Gene Proteins Generations Genes Goals Hazardous Chemicals Induction of Apoptosis Knowledge Malignant Neoplasms Malignant neoplasm of prostate Mesenchymal Molecular Neoplasm Metastasis PI3K/AKT Pathway interactions Phenotype Play Process Production Prostate Prostate Cancer therapy Proteomics RNA Interference Reporting Role Rubber Signal Pathway Signal Transduction Signal Transduction Inhibitor Testing Tobacco smoke Toxic effect Toxin United States anticancer research base cancer cell cancer stem cell cancer type carcinogenesis carcinogenicity cell motility combat dosage drug metabolism epithelial to mesenchymal transition erythritol anhydride fighting inhibitor insight knock-down men pre-clinical prostate cancer cell prostate cancer progression prostate cancer risk resistance mechanism stage-specific embryonic antigen 4 stem cell biomarkers three dimensional cell culture transcriptome transcriptomics tumor progression

项目摘要

Summary of molecular mechanism of prostate cancer progression Prostate cancer is the most common cancer of men in the world. Age, ethnicity, diet, gene mutations and a number of other factors are associated with increased risk for prostate cancer. However, the cellular progression of a prostate tumor cell are not well known. Diepoxybutane (DEB) is a carcinogenic metabolite of 1,3-butadiene (BD), a hazardous chemical used in rubber production and present in automobile exhaust and tobacco smoke. Efforts to understand mechanisms of BD toxicity have recently demonstrated that DEB causes the cell cycle to stop and further induces apoptosis upon binding to DNA. However, we have found that at low concentrations (0.5 µM), DEB resulted in DU145 cell migration and activates PI3K, EMT marker E-Cadherin and the Cancer Stem Cell (CSC) markers SSEA-4 and Oct3/4 in 2D cultures of DU145 prostate cancer cells but its role is unclear under 3D cell culture conditions. We hypothesize that DEB may be effective in inducing Epithelial-to-Mesenchymal Transition (EMT) and stimulates drug resistant mechanisms through the activation of specific cell signaling pathways. We will test our hypothesis by two Aims. We will first to identify the functional role of the PI3K/AKT/ mTOR cell signaling pathway in prostate cancer progression by the use of commercially available signal transduction inhibitors. We then will investigate the new molecular mechanism by which DEB promotes prostate cancer progression due to network of signaling pathways. This Aim will be conducted single-cell transcriptome (scRNAseq) and proteomic analyses (Cell signal and Apoptotic antibody arrays) on control versus DEB-treated spheroids to identify the genes/ proteins that show altered expression in prostate cancer cells exposed to DEB. Functional studies will be conducted by performing CRISPR/Cas9 knockdown or RNAi of new key gene or genes with known association with cell migration and/or acquisition of drug resistance. The results obtained from this project will help us to understand the role of DEB on prostate cancer progression and will provide an insight on anticancer drug metabolism that leads to chemotherapy resistance. Furthermore, the results obtained from this project will provide insights into new important approaches to combat prostate cancer which may also be applicable to other types of cancer. More importantly, the knowledge acquired at the conclusion of this project may enhance our ability to fight cancer progression.

前列腺癌进展的分子机制总结前列腺癌是世界上最常见的男性癌症，与年龄、种族、饮食、基因有关。突变和许多其他因素与前列腺癌风险增加有关。然而，前列腺肿瘤细胞的细胞进展尚不清楚。 (DEB) 是 1,3-丁二烯 (BD) 的致癌代谢物，1,3-丁二烯 (BD) 是一种用于橡胶的危险化学品努力了解汽车尾气和烟草烟雾中的产生和存在。 BD 毒性机制最近证明 DEB 会导致细胞周期停止并在与DNA结合后进一步诱导细胞凋亡。然而，我们发现其含量较低。浓度 (0.5 µM)，DEB 导致 DU145 细胞迁移并激活 PI3K、EMT 标记二维培养物中的 E-钙粘蛋白和癌症干细胞 (CSC) 标记物 SSEA-4 和 Oct3/4 DU145 前列腺癌细胞，但其在 3D 细胞培养条件下的作用尚不清楚。研究发现 DEB 可能有效诱导上皮间质转化 (EMT) 并通过激活特定的细胞信号传导刺激耐药机制我们将通过两个目标来检验我们的假设。我们将首先确定其功能作用。 PI3K/AKT/ mTOR 细胞信号通路在前列腺癌进展中的应用然后我们将研究市售的信号转导抑制剂。 DEB 通过信号网络促进前列腺癌进展的机制该目标将进行单细胞转录组（scRNAseq）和蛋白质组学。对对照与 DEB 处理的球体进行分析（细胞信号和凋亡抗体阵列）鉴定在暴露于的前列腺癌细胞中表现出表达的基因/蛋白质 DEB 将通过 CRISPR/Cas9 敲除或 RNAi 进行。新的关键基因或已知与细胞迁移和/或药物获取相关的基因反抗。该项目获得的结果将帮助我们了解DEB对前列腺的作用癌症进展并将提供抗癌药物代谢的见解，从而导致此外，该项目获得的结果将提供化疗耐药性。对对抗前列腺癌的新的重要方法的见解也可能适用更重要的是，在本文结束时获得的知识。项目可能会增强我们对抗癌症进展的能力。