The Par-4/PKCz complex in prostate cancer

前列腺癌中的 Par-4/PKCz 复合物

• 批准号: 7651604
• 负责人: Maria Teresa Diaz Meco Conde
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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/7651604
• 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; Oncogenes; 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; effective therapy; in vivo; indexing; men; mutant; novel; novel therapeutic intervention; prostate cancer prevention; prostate carcinogenesis; public health relevance; research study; tumor; tumor progression; tumorigenesis

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. .

简介（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。前列腺肿瘤最初对雄激素消融术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。显然，需要新的治疗方法，这将需要更好地理解控制前列腺肿瘤发生的信号事件。我们实验室发现了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起作用。我们的初步结果表明，Par-4在60%的人类前列腺肿瘤中缺失，它结合并抑制PKC6，从而降低NF-:B和Akt的激活，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PKC6表达与Ki67标记指数升高之间存在相关性。此外，通过比较PKC6在人类前列腺肿瘤不同阶段的表达水平，我们发现PKC6的表达与肿瘤的高度侵袭性密切相关。因此，Par-4/PKC6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变（PIN），当PTEN杂合缺失时，PIN可发展为前列腺腺癌。因此，Par-4可能通过PKC6作用于两条关键信号通路NF-:B和Akt，从而成为一种新的肿瘤抑制因子。本研究的长期目标是揭示前列腺癌发生和发展过程中的信号级联反应。这项工作将验证Par-4缺失与PTEN单倍功能不全会引发侵袭性前列腺癌的假设，并将确定控制这一过程的细胞和分子信号通路。对这些现象的理解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，在本提案中，我们将1)验证Par-4缺陷与PTEN杂合性联合导致侵袭性前列腺癌产生的假设；2)在PTEN单倍功能不全的情况下，确定par -4介导的参与前列腺癌进展的细胞和分子机制。这项工作将增加我们对前列腺癌发生调节机制的理解，从长远来看，将为开发新的、更具体的、毒性更小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，其发病率近年来有所增加。目前还没有有效的治疗方法，因为肿瘤对现有的药物产生了耐药性。本文主要研究新型肿瘤抑制因子Par-4在前列腺肿瘤发生控制中的体内作用及其机制。这是一个新的模型系统，将产生高度重要的信息，关于识别新的分子靶点，为前列腺癌的新治疗和诊断方法的发展。