Regulation of prostate cancer cell survival by 5-lipoxygenase:Role of PKC-epsilon

5-脂氧合酶对前列腺癌细胞存活的调节：PKC-ε 的作用

基本信息

批准号：
8517603
负责人：
JAGADANANDA GHOSH
金额：
$ 22.86万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-12 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517603
关键词：
12-HETE Age Androgens Animal Model Animals Apoptosis Arachidonate 5-Lipoxygenase BCL2 gene C57BL/6 Mouse Cancer Control Cell Fractionation Cell Survival Cells Chemicals DNA Binding Data Development Diazoxide Diet Disease Dominant-Negative Mutation Down-Regulation Epithelial Cells Gene Targeting Genetic Transcription Goals Growth Health Human Hydroxyeicosatetraenoic Acids Immunohistochemistry Induction of Apoptosis Knock-out Knockout Mice Leukotrienes Malignant Neoplasms Malignant neoplasm of prostate Measures Mediating Mediator of activation protein Mitochondria Mitosis Mus Nuclear Nude Mice Omega-6 Fatty Acids Oncogenic Oral Organelles Phosphorylation Play Prevention strategy Prevention therapy Preventive Production Prostate Prostatic Neoplasms Regulation Research Project Grants Resistance Role Series Signal Transduction Solvents Testing Therapeutic Time Toxic effect Transgenic Organisms Translations Tumor Tissue Up-Regulation Western Blotting Xenograft procedure androgen independent prostate cancer aurora kinase base design in vivo inhibitor/antagonist killings male neoplastic cell novel novel strategies overexpression prevent promoter prostate cancer cell protein kinase C epsilon research study survivin treatment duration treatment effect tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Regulation of prostate cancer cell survival by 5-lipoxygenase: Role of PKC-epsilon Fresh experimental data suggest that induction of apoptosis in prostate cancer (PCa) cells by blocking critical survival mechanism(s) can be an attractive approach to prevent and treat PCa because clinically PCa is often characterized as slow growing where anti-mitogenic therapies are not much effective. However, the repertoire of survival mechanisms in PCa cells is not completely understood which largely contributes to the loss of battle against this disease. Emerging evidence from various studies has shown that PCa cells constitutively generate metabolites of 5-lipoxygenase (5-Lox) from arachidonic acid (an omega-6 fatty acid plentiful in Western diets), and inhibition of 5-Lox by specific inhibitors blocks production of 5-Lox metabolites and induces rapid apoptosis both in androgen-sensitive as well as androgen-independent PCa cells sparing non-cancer cells. Apoptosis is effectively prevented by the 5-Lox metabolites, 5(S)-HETE and 5-oxoETE, suggesting that these metabolites play an essential role in the survival of PCa cells. A critical role of 5-Lox in the survival of PCa cells has also been documented using siRNAs against 5-Lox. However, signaling mechanism(s) through which 5-Lox metabolites regulate PCa cell survival are not yet understood. Interestingly, 5-Lox is not expressed in normal prostate glands but is highly expressed in prostate tumors and in PCa cells, which together with a critical role of 5-Lox in the survival of PCa cells, suggests that 5-Lox may play an important role in the development of PCa. A recent pilot experiment showed that MK591, a specific inhibitor of 5-Lox activity, remarkably blocks prostate tumor growth in nude mice xenografts without any toxicity to animal health, suggesting that inhibition of 5-Lox could be an attractive approach for mounting specific attack on PCa cells without general toxicity. Thus, in vivo targeting of 5-Lox should be extensively carried out for a rapid translational development against PCa. The goals of this research project are to delineate the signaling mechanisms underlying regulation of PCa cell survival by 5-Lox, and to test the in vivo effects of targeting 5-Lox focusing on both the preventive and therapeutic aspects of PCa. These goals will be achieved by accomplishing the objectives of three specific aims. Specific Aim 1 will determine how 5-Lox activity regulates PCa cell survival involving PKC-epsilon (PKC5)-mediated signaling, because inhibition of 5-Lox inhibits PKC5 which is prevented by 5-Lox metabolites, and 5-Lox inhibition-induced apoptosis is prevented by activators of PKC5. Specific Aim 2 will determine whether inhibition of 5-Lox inhibits growth of prostate tumors in nude mice xenografts via induction of apoptosis in PCa cells. Specific Aim 3 will determine the role of 5-Lox in the development and progression of PCa by generating 5-Lox knockout transgenic (TRAMP) mice. Accomplishing the goals in this research project will help us to understand a novel mechanism of PCa cell survival, to determine whether 5-Lox plays a role in the development and progression of PCa, and to test whether targeting 5-Lox could be a novel mechanism-based strategy for prevention as well as treatment of PCa.

描述（由申请人提供）：通过5-脂氧合酶对前列腺癌细胞存活的调节：PKC- EPSILON新鲜实验数据的作用表明，通过阻止关键生存机制来阻止前列腺癌（PCA）细胞中凋亡的诱导可以是预防和治疗PCA的吸引人的方法，因为临床上的PCA通常是pCA的良好表征，而在抗原中，pCA的表现却很大。但是，尚不完全了解PCA细胞中生存机制的曲目，这在很大程度上导致了与该疾病的战斗的丧失。来自各种研究的新出现的证据表明，PCA细胞组成产生5-脂氧合酶（5-lox）的蛛网膜酸（西方饮食中的omega-6脂肪酸丰富）的代谢物，并通过特定的抑制剂阻止5-lox抑制5-lox的抑制作用。细胞保留非癌细胞。 5-lox代谢物（5（s）hete和5氧化物）有效地预防了凋亡，这表明这些代谢产物在PCA细胞的存活中起着至关重要的作用。 5-lox在PCA细胞存活中的关键作用也已通过针对5-lox的siRNA进行了记录。然而，尚不清楚5-lox代谢物调节PCA细胞存活的信号传导机制。有趣的是，5-lox在正常的前列腺中不表达，而是在前列腺肿瘤和PCA细胞中高度表达，在PCA细胞存活中，这与5-LOX在PCA生存中的关键作用一起表明5-lox可能在PCA发展中起重要作用。最近的一个试点实验表明，MK591是一种5-lox活性的特异性抑制剂，明显阻断裸鼠异种移植物中前列腺肿瘤的生长而没有对动物健康毒性的任何毒性，这表明抑制5-lox可能是在没有普通毒性的情况下对PCA细胞上安装特定攻击的一种有吸引力的方法。因此，应广泛执行5-lox的体内靶向，以快速对PCA进行转化。该研究项目的目标是描述PCA细胞存活的信号传导机制通过5-LOX，并测试靶向5-lox的体内效应，以PCA的预防和治疗方面均以PCA的预防和治疗性方面的效果。这些目标将通过实现三个特定目标的目标来实现。具体目标1将确定5-LOX活性如何调节涉及PKC-EPSILON（PKC5）介导的信号传导的PCA细胞存活，因为抑制5-LOX抑制PKC5，这是由5-lox代谢物和5-lox抑制诱导的凋亡预防的PKC5。具体目标2将确定抑制5-LOX是否通过诱导PCA细胞凋亡抑制裸鼠异种移植物中前列腺肿瘤的生长。特定的目标3将通过产生5-lox敲除转基因（Tramp）小鼠来确定5-LOX在PCA的发展和进展中的作用。在该研究项目中实现目标将有助于我们了解PCA细胞存活的新型机制，以确定5-LOX是否在PCA的开发和发展中起作用，并测试靶向5-LOX是否可以成为基于预防机制的新型策略以及PCA的处理。