Mechanism of cancer progression in prostate cancer cells

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还不是很清楚。二环氧丁烷 (Deb)是1，3-丁二烯(BD)的致癌代谢产物，1，3-丁二烯是橡胶中使用的危险化学品 生产和存在于汽车尾气和烟草烟雾中。努力了解 BD毒性的机制最近证明，DEB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，在低水平 浓度(0.5µM)，DEB导致DU145细胞迁移并激活PI3K，EMT标志物 E-钙粘附素与肿瘤干细胞(CSC)标志物SSEA-4和Oct3/4在2D培养中的表达 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。我们 假设DEB可能有效地诱导上皮细胞向间充质细胞转化(EMT) 并通过激活特定的细胞信号来刺激耐药机制 小路。我们将通过两个目标来检验我们的假设。我们将首先确定 PI3K/AKT/mTOR细胞信号通路在前列腺癌进展中的作用 商业上可获得的信号转导抑制剂。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 小路。这一目标将进行单细胞转录组(ScRNAseq)和蛋白质组学 对照和DEB处理的球体的分析(细胞信号和凋亡抗体阵列) 确定暴露于前列腺癌的细胞中表达改变的基因/蛋白 黛比。功能研究将通过执行CRISPR/Cas9基因敲除或RNAi来进行 一个或多个已知与细胞迁移和/或药物获得相关的新关键基因 抵抗。 从这个项目中获得的结果将有助于我们理解DEB在前列腺中的作用 癌症进展，并将提供关于抗癌药物代谢的洞察，从而导致 化疗耐药。此外，该项目取得的成果将提供 对对抗前列腺癌的新的重要方法的见解，这些方法可能也适用 其他类型的癌症。更重要的是，在此结束时获得的知识 该项目可能会增强我们抗击癌症进展的能力。

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.