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

• 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
• 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

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-脂氧合酶调节前列腺癌细胞存活：PKC-ε 的作用新的实验数据表明，通过阻断关键存活机制诱导前列腺癌（PCa）细胞凋亡可能是预防和治疗 PCa 的一种有吸引力的方法，因为临床上 PCa 的特征通常是生长缓慢，而抗有丝分裂疗法不太有效。然而，PCa 细胞的全部生存机制尚未完全了解，这在很大程度上导致了与这种疾病的斗争的失败。来自各种研究的新证据表明，PCa 细胞从花生四烯酸（西方饮食中富含的一种 omega-6 脂肪酸）组成性地产生 5-脂氧合酶 (5-Lox) 代谢物，并且通过特定抑制剂抑制 5-Lox 可阻止 5-Lox 代谢物的产生，并诱导雄激素敏感型和雄激素非依赖性 PCa 的快速细胞凋亡 细胞不伤害非癌细胞。 5-Lox 代谢物 5(S)-HETE 和 5-oxoETE 可有效防止细胞凋亡，表明这些代谢物在 PCa 细胞的存活中发挥重要作用。使用针对 5-Lox 的 siRNA 也记录了 5-Lox 在 PCa 细胞存活中的关键作用。然而，5-Lox 代谢物调节 PCa 细胞存活的信号传导机制尚不清楚。有趣的是，5-Lox 在正常前列腺中不表达，但在前列腺肿瘤和 PCa 细胞中高表达，再加上 5-Lox 在 PCa 细胞存活中的关键作用，表明 5-Lox 可能在 PCa 的发生发展中发挥重要作用。最近的一项初步实验表明，MK591（一种 5-Lox 活性的特异性抑制剂）可显着阻止裸鼠异种移植物中前列腺肿瘤的生长，且对动物健康没有任何毒性，这表明抑制 5-Lox 可能是对 PCa 细胞进行特异性攻击且无一般毒性的一种有吸引力的方法。因此，应广泛开展 5-Lox 的体内靶向研究，以实现针对 PCa 的快速转化开发。该研究项目的目标是描绘 5-Lox 调节 PCa 细胞存活的信号传导机制，并测试靶向 5-Lox 的体内效果，重点关注 PCa 的预防和治疗方面。这些目标将通过实现三个具体目标来实现。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 5-Lox 的抑制会抑制 PKC5，而 5-Lox 代谢物可阻止 PKC5，而 PKC5 激活剂可阻止 5-Lox 抑制诱导的细胞凋亡。具体目标 2 将确定抑制 5-Lox 是否会通过诱导 PCa 细胞凋亡来抑制裸鼠异种移植物中前列腺肿瘤的生长。具体目标 3 将通过生成 5-Lox 敲除转基因 (TRAMP) 小鼠来确定 5-Lox 在 PCa 发生和进展中的作用。完成该研究项目的目标将有助于我们了解PCa细胞存活的新机制，确定5-Lox是否在PCa的发生和进展中发挥作用，并测试靶向5-Lox是否可以成为预防和治疗PCa的一种新的基于机制的策略。