The Par-4/PKCz complex in prostate cancer

前列腺癌中的 Par-4/PKCz 复合物

• 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
• 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

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.

项目摘要 前列腺癌是西方国家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疗法的反应良好，但有时不依赖雄激素 没有有效治疗的阶段。显然，需要新的疗法方法，这将需要更好 了解控制前列腺肿瘤发生的信号事件。 我们的实验室已经确定了一种新的肿瘤抑制剂Par-4，该肿瘤具有促凋亡活性并发挥作用 在人前列腺肿瘤发生中的作用。我们的初步结果表明，第4杆的60％在60％ 人类前列腺肿瘤，并结合并抑制PKC。因此减少了NF-€和Akt激活， 并增加细胞死亡。有趣的是，人类前列腺癌的组织微阵列分析显示 PKC表达与增加Ki67标记指数之间的相关性。此外，癌症基因表达 比较人类前列腺肿瘤不同阶段中PKC？ 与高度的肿瘤侵袭性密切相关。因此，Par-4/pkc？ 似乎是前列腺肿瘤发生的相关候选介体。在初步研究中，我们发现 PAR-4 - / - 小鼠发展了良性增生和前列腺内肿瘤（PIN），可以发展为 前列腺腺癌与PTEN杂合缺失结合使用。因此，第4杆作为一个 新型肿瘤抑制器通过其撞击两个关键信号通路NF- - B和AKT的能力，可能 通过pkc¿。 这里提出的研究的长期目标是揭示参与前列腺的信号传导级联 癌症的启动和进展。这项工作将测试以下假设 PTEN单倍不足诱导侵入性前列腺腺癌，并将确定细胞和细胞 控制该过程的分子信号通路。理解这些现象的进步 可能会发现有关前列腺癌发生的新观点，并为前列腺癌提供新的目标 预防，诊断和治疗。因此，在此提案中，我们将1）检验以下假设：Par-4 与PTEN杂合性结合的缺乏会导致浸润性前列​​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单倍不足的背景下进展。这项工作将增加我们对 调节前列腺癌发生的机制，从长远来看将提供 开发新颖，更具体，因此毒性较小的疗法所必需的知识 治疗前列腺癌。