The Par-4/PKCz complex in prostate cancer

前列腺癌中的 Par-4/PKCz 复合物

基本信息

批准号：
8318275
负责人：
Maria Teresa Diaz Meco Conde
金额：
$ 38.44万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-12 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318275
关键词：
Ablation Accounting Androgens Antiandrogen Therapy Apoptotic Benign Prostatic Hypertrophy Binding Biological Models Cell Culture Techniques Cell Death Cell Line Cell Proliferation Cells Complement Complex Country Development Diagnosis Diagnostic Dominant-Negative Mutation Event Gene Expression Generations Goals Growth Human Incidence Intraepithelial Neoplasia Investigation Knowledge Label Laboratories Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Microarray Analysis Modeling Molecular Molecular Profiling Molecular Target Mus Mutant Strains Mice Neoplasms PAWR gene PTEN gene Pharmaceutical Preparations Phenotype Play Process Property Prostate Prostate Adenocarcinoma Prostate carcinoma Prostatic Neoplasms Regulation Resistance development Role Signal Pathway Signal Transduction Signaling Molecule Staging Testing Tissue Microarray Tumor Suppressor Proteins Work cancer gene expression cancer initiation cancer type cell transformation effective therapy in vivo indexing men mutant novel novel therapeutic intervention prostate cancer prevention prostate carcinogenesis research study tumor tumor progression tumorigenesis

项目摘要

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.

项目概要前列腺癌是西方国家男性最常见的恶性肿瘤。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状态显然，需要新的治疗方法，这需要更好的治疗方法。了解控制前列腺肿瘤发生的信号事件。我们实验室鉴定出一种新的抑癌基因Par-4，具有促凋亡活性，可发挥我们的初步结果表明，Par-4 在 60% 的前列腺癌中丢失。人类前列腺肿瘤，并且它结合并抑制 PKC¿ ，从而减少 NF-¿ B 和 Akt 激活，人类前列腺癌的组织微阵列分析揭示了细胞死亡的增加。 PKC之间的相关性¿表达和增加的 Ki67 标记指数此外，癌症基因表达。配置文件比较 PKC¿人类前列腺肿瘤不同阶段的水平表明 PKC¿表达与高度的肿瘤侵袭性密切相关，因此，Par-4/PKC¿复杂的在初步研究中，我们发现似乎是前列腺肿瘤发生的相关候选介质。 Par-4-/- 小鼠出现良性增生和前列腺上皮内瘤变 (PIN)，并可能进展为前列腺腺癌与 PTEN 杂合缺失相结合，因此，Par-4 成为一种突变。新型肿瘤抑制因子，能够影响两个关键信号通路 NF-¿ B 和 Akt，可能通过 PKC¿ 。这里提出的研究的长期目标是解开前列腺中涉及的信号级联这项工作将检验 Par-4 的缺失与癌症的发生和进展相结合的假设。 PTEN 单倍体不足会引发侵袭性前列腺癌，并将决定细胞和控制该过程的分子信号传导途径。可能揭示前列腺癌发生的新视角，并为前列腺癌提供新靶点因此，在本提案中，我们将 1) 检验 Par-4 的假设。缺陷与 PTEN 杂合性结合导致侵袭性前列腺癌的产生；2) 确定 Par-4 介导的前列腺癌相关细胞和分子机制这项工作将增加我们对 PTEN 单倍体不足的理解。参与前列腺癌发生调节的机制，从长远来看将提供开发新的、更具体的、因此毒性较小的治疗方法所必需的知识治疗前列腺癌。