The role of PKD3 in prostate carcinogenesis

PKD3在前列腺癌发生中的作用

• 批准号: 8228087
• 负责人: Qiming Jane Wang
• 金额: $ 30.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228087
• 关键词: 1,2-diacylglycerol; Acetates; Address; Affect; Animal Model; Binding Proteins; Biological Assay; Biological Markers; Cancer Cell Growth; Cancer Etiology; Cell Cycle Progression; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Cellular biology; Clinical; Complex; Coupled; Couples; Cytoplasm; DAG/PE-Binding Domain; Development; Diglycerides; Disease; Etiology; Event; Family; Future; Goals; Growth; HSPB1 gene; Health; Human; Knowledge; MAPK14 gene; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Mus; Neoplasm Metastasis; Nuclear; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Phorbol Esters; Phosphorylation; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Protein Isoforms; Protein Kinase C; Protein-Serine-Threonine Kinases; Proteins; Regulatory Pathway; Research; Resistance; Role; Screening procedure; Second Messenger Systems; Signal Pathway; Signal Transduction; Testing; Therapeutic; Transgenic Organisms; Tumor Tissue; analog; base; cancer cell; cell growth; cell type; design; in vivo; insight; mTOR Signaling Pathway; member; migration; mouse model; novel; novel marker; phorbol-12-myristate; prevent; prognostic; prostate carcinogenesis; protein kinase D; response; second messenger; therapeutic target; treatment strategy; tumor; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): This proposal investigates novel signaling mechanisms of protein kinase D (PKD) and its relevance to the pathogenesis of prostate cancer. The family of PKD serine/threonine kinases is a novel target of the key second messenger diacylglycerol (DAG) and its pharmacological analogs, phorbol esters. DAG and phorbol esters directly bind PKD at its C1 domain and activate PKD through phosphorylation via protein kinase C (PKC). Aberrant DAG signaling is closely couples to the etiology of many cancers including the prostate cancer. PKD as a novel DAG target has significant prognostic and therapeutic values for these diseases. Substantial evidence from our studies supports a novel role of PKD3, a new member of the PKD family, in prostate carcinogenesis. We have demonstrated progressive nuclear accumulation of PKD3 as well as elevated expression in human prostate tumors, revealing a potential mechanism whereby PKD contributes to the development of prostate cancer. PKD3 promotes prostate cancer cell growth, survival, and migration/invasion, and knockdown of PKD3 inhibits the growth of prostate tumor xenografts in mice. PKD3 signals downstream of PKC5, an oncogenic protein in prostate cancer, and modulates crucial cell growth/survival regulatory pathways including Akt and EKR1/2 in prostate cancer cells. These findings support the crucial role of a constitutively active PKC5/PKD3 pathway in prostate oncogenesis. The proposed studies will further dissect the signaling mechanisms of PKD3 and define its functional impact in the pathogenesis of prostate cancer. If successful, these studies will reveal the potential value of PKD3 as a novel biomarker and therapeutic target for prostate cancer. Ultimately, new strategies may be designed for targeting PKD3 as therapy for prostate cancer as well as other diseases with deregulated DAG signaling. Three specific aims will be tested in this proposal: Specific Aim 1. Determine the role of PKD3 in the pathogenesis of prostate cancer in vivo. Specific Aim 2. Test the hypothesis that the nuclear accumulation of PKD3 as a consequence of constitutively active PKC5/PKD3 is essential for growth, survival, migration/invasion of prostate cancer cells. Specific Aim 3. Determine relevance of PKD3 in acquired phorbol 12-myristate 13-acetate (PMA) resistance and cell proliferation in prostate cancer cells. PUBLIC HEALTH RELEVANCE: The PKD family, as a novel target of diacylglycerol and an effector of PKC, promotes cell growth and survival. PKD has also been implicated in hyperproliferative disorders and cancer. We hypothesize that PKD3 promotes prostate cancer development via a novel signaling pathway involving PKC5/PKD3-mediated activation of Akt and ERK1/2. This research will define the relevance of PKD3 to the pathogenesis of prostate cancer and identify the signaling mechanisms by which PKD3 promotes tumor development. The ultimate goal of this project is to assess the value of PKD3 as a novel marker and/or therapeutic target for prostate cancer. Fundamental new knowledge will be obtained concerning mechanisms of prostate oncogenesis thereby facilitating future design of novel treatment strategies to limit or prevent this deadly disease.

描述（由申请人提供）：该提案研究了蛋白激酶D（PKD）的新型信号传导机制及其与前列腺癌发病机理的相关性。 PKD丝氨酸/苏氨酸激酶家族是关键的第二信使二酰基甘油（DAG）及其药理学类似物Phorbol酯的新目标。 DAG和Phorbol酯在其C1结构域直接结合PKD，并通过蛋白激酶C（PKC）通过磷酸化激活PKD。异常的DAG信号传导与包括前列腺癌在内的许多癌症的病因密切相关。 PKD作为一种新的DAG靶标的这些疾病具有明显的预后和治疗价值。我们研究的大量证据支持PKD家族的新成员PKD3在前列腺致癌作用中的新作用。我们已经证明了PKD3的进行性核积累以及人类前列腺肿瘤中的表达升高，揭示了PKD有助于前列腺癌发展的潜在机制。 PKD3促进前列腺癌细胞的生长，生存和迁移/侵袭，而敲低PKD3抑制了小鼠前列腺肿瘤异种移植物的生长。 PKD3信号是PKC5的下游，PKC5是前列腺癌中的致癌蛋白，并调节了前列腺癌细胞中包括AKT和EKR1/2在内的关键细胞生长/包括AKT和EKR1/2的关键细胞生长/生存调节途径。这些发现支持了前列腺肿瘤发生中组成型活性PKC5/PKD3途径的关键作用。拟议的研究将进一步剖析PKD3的信号传导机制，并定义其在前列腺癌发病机理中的功能影响。如果成功，这些研究将揭示PKD3作为前列腺癌的新生物标志物和治疗靶标的潜在值。最终，可以设计新策略，以靶向PKD3作为前列腺癌以及其他带有DAG信号的疾病的疗法。在此提案中将测试三个具体目标：具体目标1。确定PKD3在体内前列腺癌发病机理中的作用。具体目的2。检验以下假设：组成性活跃的PKC5/PKD3导致PKD3的核积累对于生长，生存，迁移/入侵前列腺癌细胞至关重要。具体目的3。确定PKD3在获得的佛波尔12-羟基含量13-乙酸酯（PMA）耐药性和细胞增殖中的相关性。公共卫生相关性：PKD家族是二酰基甘油的新靶标和PKC的效应子，可促进细胞生长和生存。 PKD也与增殖性疾病和癌症有关。我们假设PKD3通过涉及PKC5/PKD3介导的AKT和ERK1/2激活的新型信号通路促进了前列腺癌的发展。这项研究将定义PKD3与前列腺癌发病机理的相关性，并确定PKD3促进肿瘤发育的信号传导机制。该项目的最终目标是评估PKD3作为前列腺癌的新颖标志和/或治疗靶标的价值。将获得有关前列腺肿瘤发生机制的基本新知识，从而促进了新型治疗策略的未来设计，以限制或预防这种致命的疾病。