Mechanism of cancer progression in prostate cancer cells

前列腺癌细胞的癌症进展机制

• 批准号: 10579218
• 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
• 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/10579218
• 关键词: 1,3-Butadiene; 3-Dimensional; Age; Antibodies; Antineoplastic Agents; 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; Epithelium; Ethnic Origin; Exposure to; FRAP1 gene; Gene Mutation; Generations; Genes; Goals; Hazardous Chemicals; Induction of Apoptosis; Knowledge acquisition; Malignant Neoplasms; Malignant neoplasm of prostate; Mesenchymal; Molecular; Neoplasm Metastasis; PI3K/AKT; PIK3CG gene; Pathway interactions; Phenotype; Play; Process; Production; Prostate; Prostate Cancer therapy; Proteins; Proteomics; RNA Interference; Reporting; Role; Rubber; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Testing; Tobacco smoke; Toxic effect; Toxin; Tumor Promotion; United States; acquired drug resistance; anticancer research; 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; meter; 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

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综述 前列腺癌是世界上最常见的男性癌症。年龄种族饮食基因 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并不为人所知。二环氧丁烷 (DEB)是1，3-丁二烯（BD）的致癌代谢物，BD是橡胶中使用的危险化学品 产生并存在于汽车尾气和烟草烟雾中。在学懂弄通 BD毒性的机制最近已经证明DEB导致细胞周期停止 并在与DNA结合时进一步诱导细胞凋亡。然而，我们发现，在低 浓度（0.5 µM），DEB导致DU 145细胞迁移并激活PI 3 K，EMT标志物 E-Cadherin和癌症干细胞（CSC）标志物SSEA-4和Oct 3/4在2D培养物中的表达 DU 145前列腺癌细胞，但其在3D细胞培养条件下的作用尚不清楚。我们 假设DEB可以有效诱导上皮向间充质转化（EMT） 并通过激活特定的细胞信号刺激耐药机制 途径。我们将通过两个目标来检验我们的假设。我们将首先确定 前列腺癌进展中的PI 3 K/AKT/ mTOR细胞信号传导途径， 市售的信号转导抑制剂。然后我们将研究新的分子 DEB通过信号网络促进前列腺癌进展的机制 途径。本目标将进行单细胞转录组（scRNAseq）和蛋白质组学 对对照与DEB处理的球状体的分析（细胞信号和凋亡抗体阵列）， 鉴定在暴露于以下物质的前列腺癌细胞中显示改变的表达的基因/蛋白质： 黛比功能研究将通过进行CRISPR/Cas9敲低或RNAi来进行。 新的关键基因或已知与细胞迁移和/或药物获得相关的基因 阻力 本研究的结果将有助于我们了解DEB在前列腺中的作用 癌症进展，并将提供抗癌药物代谢的见解， 化疗耐药性此外，该项目所取得的成果将提供 深入了解对抗前列腺癌的新的重要方法， 其他类型的癌症。更重要的是，在这个结论中获得的知识 该项目可能会增强我们对抗癌症进展的能力。