The Par-4/PKCz complex in prostate cancer

项目摘要 前列腺癌是西方国家男性中最常见的恶性肿瘤。前列腺肿瘤最初 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 没有有效治疗的阶段。显然，需要新的治疗方法，这将需要更好的 了解控制前列腺肿瘤发生的信号事件。 我们的实验室已经鉴定出一种新的肿瘤抑制因子Par-4，它具有促凋亡活性， 在人类前列腺肿瘤发生中的作用。我们的初步结果表明，Par-4在60%的 人前列腺肿瘤，并结合和抑制PKC，从而降低NF-B和Akt活化， 增加细胞死亡。有趣的是，人类前列腺癌的组织微阵列分析显示， PKC的表达与Ki 67标记指数的增加之间的相关性。此外，癌症基因表达 比较不同阶段的人前列腺肿瘤中PKC水平的概况表明，PKC表达 与肿瘤的高度侵袭性密切相关。因此，Par-4/PKC复合物 似乎是前列腺肿瘤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形成（PIN）， 前列腺癌与PTEN杂合缺失的组合。因此，Par-4作为一种 一种新的肿瘤抑制剂，通过其影响两个关键信号通路NF-B和Akt的能力，可能 通过PKC。 本文提出的研究的长期目标是解开前列腺增生中涉及的信号级联反应。 癌症的发生和发展。这项工作将测试假设，即Par-4的损失与 PTEN单倍不足触发浸润性前列腺癌，并将决定细胞和 控制这个过程的分子信号通路。对这些现象的理解的进展 可能揭示前列腺癌发生的新观点，并为前列腺癌提供新的靶点 预防、诊断和治疗。因此，在本提案中，我们将1）检验Par-4 与PTEN杂合性组合的缺陷导致侵袭性前列腺癌的产生;和2） 确定参与前列腺癌的Par-4介导的细胞和分子机制 在PTEN单倍不足的情况下进展。这项工作将增加我们对 参与前列腺癌发生的调节机制，并在长期内将提供 开发新的，更具体的，因此毒性较小的治疗所需的知识 前列腺癌的治疗

Project Summary 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 PKC¿, consequently reducing NF-¿B and Akt activation, and increasing cell death. Interestingly, tissue microarray analysis of human prostate carcinomas revealed a correlation between PKC¿ expression and increased Ki67 labeling indexes. Moreover, cancer gene-expression profiles comparing PKC¿ levels in different stages of human prostate neoplasias showed that PKC¿ expression was strongly correlated with a high degree of tumor aggressiveness. Therefore, the Par-4/PKC¿ 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 PKC¿. 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.