Oxidative stress-induced cellular survival pathways in prostate cancer

流行病学研究表明，非裔美国人（AA）男性的临床发病率最高， 前列腺癌（PCa）是世界上最严重的癌症。AA男性被诊断为晚期PCa， 他们的年龄更小，死亡率也更高。越来越多的证据表明， 脂肪是前列腺癌发展的重要外源性危险因素，尤其是AA男性。大量摄入 膳食脂肪似乎有助于PCa的发展，随着时间的推移驱动生产：1）分子 其增强细胞增殖和血管生成，并影响炎症;和2）活性氧物质 (ROS)从而在前列腺中产生氧化应激增强的状态。前列腺细胞适应这种情况 通过激活应激/生存信号通路，促进对氧化应激诱导的 死亡一个全面的分子方法来了解增加的生物学基础， 迫切需要AA男性的PCa发病率和死亡率来消除这些差异。我们的长期目标 是通过研究氧化应激依赖的细胞， 前列腺中激活的生存途径。该项目的重点是透镜上皮来源的 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， 在前列腺肿瘤中过表达，并促进对氧化应激诱导的细胞死亡的抵抗。我们 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 通过激活一种新的生存途径，涉及控制细胞氧化还原环境的应激基因。的 具体目标是：（1）鉴定前列腺癌中受LEDGF/p75调节的应激/氧化还原基因 （2）证明LEDGF/p75调节的应激/氧化还原基因在细胞中的表达升高， 前列腺癌组织和细胞，并促进对氧化应激诱导的细胞死亡的抗性;和（3） 证明LEDGF/p75及其调节的特异性应激/氧化还原基因的功能失活 使PCa细胞对氧化应激诱导的死亡敏感。实验方法包括以路径为重点的 DMA微阵列分析、实时PCR、转录报告基因测定、组织微阵列分析和RNA 抑制作用这项工作是创新的，因为它关注的是PCa细胞对前列腺癌耐药的新途径。 LEDGF/p75介导的氧化应激诱导的死亡，这可能是一个重要的组成部分， PCa发病率和死亡率差异的分子基础。这些研究都是高度相关的 因为它们很可能导致临床前发展的新的治疗策略，先进的 靶向LEDGF/p75介导的存活途径的PCa。他们还预计将产生宝贵的 可用于设计社区参与性预防干预措施的信息， 在南加州内陆帝国减少PCa发病率和死亡率的差异。

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.