Oxidative stress-induced cellular survival pathways in prostate cancer

流行病学研究表明，非洲裔美国人(AA)男性的临床发病率最高。 世界上被检测到的前列腺癌(PCA)。AA患者被诊断为晚期前列腺癌 年龄越小，他们的死亡率也明显更高。越来越多的证据表明膳食摄入量过高 脂肪是前列腺癌发生的一个重要的外源性风险因素，尤其是在AA男性中。高摄入量 饮食脂肪似乎有助于前列腺癌的发展，因为随着时间的推移，它推动了以下分子的产生： 促进细胞增殖和血管生成，并影响炎症；以及2)活性氧 (ROS)在前列腺中产生一种增强的氧化应激状态。前列腺细胞适应了这一点 通过激活压力/生存信号通路促进对氧化应激的抗性来应对环境 死亡。一种全面的分子方法来了解增生性心脏病的生物学基础 为了消除这些差异，迫切需要AA男性的前列腺癌发病率和死亡率。我们的长期目标 是通过研究氧化应激依赖的细胞来理解这些差异的生物学基础 生存通路在前列腺中被激活。这个项目的重点是晶状体上皮细胞来源的 75千道尔顿的生长因子(LEDGF/p75)，一种受氧化应激调节的转录因子，即 在前列腺癌中过度表达，并促进对氧化应激诱导的细胞死亡的抵抗。我们的 假设LEDGF/p75促进前列腺癌细胞对氧化应激诱导的死亡的抵抗 通过激活一条新的生存途径，涉及控制细胞氧化还原环境的应激基因。这个 目的：(1)识别前列腺癌中受LEDGF/p75调控的应激/氧化还原基因 细胞；(2)LEDGF/p75调控的应激/氧化还原基因在 前列腺癌组织和细胞，并促进抵抗氧化应激诱导的细胞死亡；以及(3) 证明LEDGF/p75及其调控的特定应激/氧化还原基因的功能失活 使前列腺癌细胞对氧化应激诱导的死亡敏感。实验方法包括以通路为中心 DMA微阵列分析、实时聚合酶链式反应、转录报告分析、组织微阵列分析和RNA 抑制力。这项拟议的工作具有创新性，因为它关注了一种新的PCA细胞抵抗 由LEDGF/p75介导的氧化应激诱导的死亡可能是ARI的重要组成部分 前列腺癌发病率和死亡率差异的分子基础。这些研究具有很高的相关性 因为它们可能导致晚期癌症新的治疗策略的临床前开发 针对LEDGF/p75介导的生存通路的PCA。预计它们还将生产出有价值的 可用于设计社区参与性预防干预措施的信息 在减少南加州内陆帝国前列腺癌发病率和死亡率方面的差距。

Epidemiological studies demonstrate that African-American (AA) men have the highest incidence of clinically detected prostate cancer (PCa) in the world. AA men are diagnosed with advanced PCa at a significantly younger age, and their mortality is also significantly higher. Growing evidence points to high intake of dietary fat as an important exogenous risk factor in PCa development, particularly among AA men. High intake of dietary fat appears to contribute to PCa development by driving the production over time of: 1) molecules that enhance cell proliferation and angiogenesis, and influence inflammation; and 2) reactive oxygen species (ROS) that produce a state of augmented oxidative stress in the prostate. Prostate cells adapt to this environment by activating stress/survival signaling pathways that promote resistance to oxidative stressinduced death. A comprehensive molecular approach to understand the biological basis of the increased PCa incidence and mortality in AA men is critically needed to eliminate these disparities. Our long-term goal is to understand the biological basis of these disparities by studying oxidative stress-dependent cellular survival pathways activated in the prostate. The focus of this project is the lens epithelium-derived growth factor of 75 kilodaltons (LEDGF/p75), a transcription factor regulated by oxidative stress that is overexpressed in prostate tumors and promotes resistance to oxidative stress-induced cell death. Our hypothesis is that LEDGF/p75 promotes prostate cancer cell resistance to oxidative stress-induced death by activating a novel survival pathway involving stress genes controlling the cellular redox environment. The specific aims are designed to: (1) identify stress/redox genes regulated by LEDGF/p75 in prostate cancer cells; (2) demonstrate that stress/redox genes regulated by LEDGF/p75 have elevated expression in prostate cancer tissue and cells and promote resistance to oxidative stress-induced cell death; and (3) demonstrate that functional inactivation of LEDGF/p75 and specific stress/redox genes it regulates sensitizes PCa cells to oxidative stress-induced death. Experimental approaches include pathway-focused DMA microarray analysis, real-time PCR, transcription reporter assays, tissue microarray analysis, and RNA inhibition. The proposed work is innovative because it focuses on a novel pathway of PCa cell resistance to oxidative stress-induced death, mediated by LEDGF/p75, which could be ari important component of the molecular basis for the disparities in PCa incidence and mortality. These studies are highly relevant because they are likely to lead to the preclinical development of novel therapeutic strategies for advanced PCa targeting the LEDGF/p75-mediated survival pathway. They are also expected to yield valuable information that could be used for the design of community-participatory preventive interventions aimed at reducing the disparities in the incidence and mortality of PCa in the Inland Empire of Southern California.