The Par-4/PKCz complex in prostate cancer

描述(申请人提供)：前列腺癌是西方国家男性中最常见的恶性肿瘤。前列腺癌最初对雄激素消融或抗雄激素治疗反应良好，但最终进入雄激素非依赖性阶段，没有有效的治疗方法。显然，需要新的治疗方法，这将需要更好地了解控制前列腺癌发生的信号事件。我们的实验室已经发现了一种新的肿瘤抑制因子PAR-4，它具有促细胞凋亡的活性，在人类前列腺癌的发生中发挥作用。我们的初步结果表明，在60%的人类前列腺肿瘤中，PAR-4缺失，并且它结合并抑制PKC6，从而减少了NF-：B和Akt的激活，并增加了细胞死亡。有趣的是，对人类前列腺癌的组织微阵列分析显示，PKC6的表达与Ki67标记指数增加之间存在相关性。此外，比较人类前列腺癌不同阶段的PKC6水平的癌症基因表达谱显示，PKC6的表达与肿瘤的高度侵袭性密切相关。因此，PAR-4/PKC6复合体可能是前列腺癌发生的相关候选介质。在初步研究中，我们发现PAR-4-/-小鼠出现良性增生和前列腺上皮内瘤变(PIN)，当与PTEN杂合缺失结合时，可能进展为前列腺癌。因此，PAR-4作为一种新的肿瘤抑制因子，可能通过PKC6作用于两条重要的信号通路--核因子：B和Akt。这里提出的研究的长期目标是解开前列腺癌发生和发展中涉及的信号级联反应。这项工作将检验这样一种假设，即PAR-4的缺失与PTEN单倍体不足共同触发侵袭性前列腺癌，并将确定控制这一过程的细胞和分子信号通路。了解这些现象的进展可能会揭示前列腺癌发生的新视角，并为前列腺癌的预防、诊断和治疗提供新的靶点。因此，在这项建议中，我们将1)检验PAR-4缺乏与PTEN杂合性导致侵袭性前列腺癌的产生的假设；2)在PTEN单倍性不足的情况下，确定PAR-4介导的细胞和分子机制参与前列腺癌的进展。这项工作将增加我们对前列腺癌发生调控机制的理解，从长远来看，将为开发新的、更特异的、毒性更低的前列腺癌治疗方法提供必要的知识。公共卫生相关性：前列腺癌是西方国家男性中最常见的癌症类型，近年来其发病率有所上升。目前，由于肿瘤对现有药物产生抗药性，目前还没有有效的治疗方法。本研究旨在了解新型肿瘤抑制因子PAR-4在控制前列腺癌发生中的体内作用和作用机制。这是一个新的模型系统，将产生关于识别新的分子靶点的非常重要的信息，用于开发前列腺癌的新疗法和诊断方法。。

DESCRIPTION (provided by applicant): Prostate cancer is the most common malignancy among men in western countries. Prostate tumors initially respond well to androgen ablation or anti-androgen therapy, but eventually enter an androgen-independent stage with no effective therapy. Clearly, new therapeutic approaches are needed, and this will require a better understanding of the signaling events that control prostate tumorigenesis. Our laboratory has identified a new tumor suppressor, Par-4, which has pro-apoptotic activity and plays a role in human prostate tumorigenesis. Our preliminary results have demonstrated that Par-4 is lost in 60% of human prostate tumors, and that it binds and inhibits PKC6, consequently reducing NF-:B and Akt activation, and increasing cell death. Interestingly, tissue microarray analysis of human prostate carcinomas revealed a correlation between PKC6 expression and increased Ki67 labeling indexes. Moreover, cancer gene-expression profiles comparing PKC6 levels in different stages of human prostate neoplasias showed that PKC6 expression was strongly correlated with a high degree of tumor aggressiveness. Therefore, the Par-4/PKC6 complex appears to be a relevant candidate mediator of prostate tumorigenesis. In preliminary studies, we found that Par-4-/- mice developed benign hyperplasia and prostate intraepithelial neoplasias (PIN) that could progress to prostate adenocarcinomas when combined with PTEN heterozygous deletion. Therefore, Par-4 emerges as a novel tumor suppressor through its ability to impinge on two critical signaling pathways, NF-:B and Akt, likely through PKC6. The long-term goal of the studies proposed here is to unravel the signaling cascades involved in prostate cancer initiation and progression. This work will test the hypothesis that the loss of Par-4 in combination with PTEN haploinsufficiency triggers invasive prostate adenocarcinoma, and will determine the cellular and molecular signaling pathways that control that process. Advances in the understanding of these phenomena may uncover new perspectives on prostate carcinogenesis, and provide novel targets for prostate cancer prevention, diagnosis, and therapy. Therefore, in this proposal we will 1) test the hypothesis that Par-4 deficiency in combination with PTEN heterozygosity leads to the generation of invasive prostate cancer; and 2) determine the Par-4-mediated cellular and molecular mechanisms that are involved in prostate cancer progression in the context of PTEN haploinsufficiency. This work will increase our understanding of the mechanisms involved in the regulation of prostate carcinogenesis, and in the long term will provide the knowledge necessary for the development of novel, more specific, and thus less toxic, therapies for the treatment of prostate cancer. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common type of cancer among men in western countries, and its incidence has increased in recent years. Currently, there is no efficient treatment because tumors develop resistance to the available drugs. This proposal is focused on understanding the in vivo role and mechanism of action of Par-4, a novel tumor suppressor, in the control of prostate tumorigenesis. This is a novel model system that will generate highly significant information regarding the identification of new molecular targets for the development of novel therapies and diagnostic approaches for prostate cancer. .