The role of PKD3 in prostate carcinogenesis

PKD3在前列腺癌发生中的作用

• 批准号: 7633521
• 负责人: Qiming Jane Wang
• 金额: $ 31.44万
• 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/7633521
• 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; Cells; Cellular biology; Clinical; Complex; Coupled; Couples; Cytoplasm; DAG/PE-Binding Domain; Development; Diglycerides; Disease; Etiology; Event; Family; Future; Goals; Growth; Human; Knowledge; MAPK14 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; public health relevance; 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)：这项建议研究蛋白激酶D(PKD)的新信号机制及其与前列腺癌发病机制的相关性。PKD丝氨酸/苏氨酸激酶家族是关键的第二信使二酰甘油(DAG)及其类似物佛波酯的新靶点。DAG和佛波酯与PKD的C1区直接结合，通过蛋白激酶C(PKC)的磷酸化激活PKD。DAG信号的异常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靶点，对这些疾病具有重要的预后和治疗价值。来自我们研究的大量证据支持PKD3在前列腺癌发生中的新作用，PKD3是PKD家族的新成员。我们已经证明了PKD3的进行性核积聚以及在人类前列腺癌中的高表达，揭示了PKD促进前列腺癌发展的潜在机制。PKD3促进前列腺癌细胞的生长、存活和迁移/侵袭，而PKD3的敲除抑制了小鼠前列腺癌移植瘤的生长。PKD3信号位于前列腺癌致癌蛋白PKC5的下游，在前列腺癌细胞中调控重要的细胞生长/生存调控通路，包括Akt和EKR1/2。这些发现支持PKC5/PKD3通路在前列腺癌发生中的关键作用。这些研究将进一步剖析PKD3的信号转导机制，明确其在前列腺癌发病机制中的作用。如果成功，这些研究将揭示PKD3作为前列腺癌新的生物标志物和治疗靶点的潜在价值。最终，可能会设计新的策略，将PKD3作为前列腺癌和其他DAG信号失控疾病的治疗药物。本研究的目的有三个：1.明确PKD3在体内前列腺癌发病机制中的作用。特定目的2.验证PKD3的核积聚是前列腺癌细胞生长、存活、迁移/侵袭所必需的假说。具体目的3.确定PKD3在前列腺癌获得性佛波醇12-肉豆蔻酸酯(PMA)耐药性和细胞增殖中的相关性。公共卫生相关性：PKD家族作为二酰甘油的新靶点和PKC的效应者，促进细胞生长和存活。PKD还与增生性疾病和癌症有关。我们假设PKD3通过一条新的信号通路促进前列腺癌的发生发展，该信号通路涉及PKC5/PKD3介导的Akt和ERK1/2的激活。本研究将确定PKD3与前列腺癌发生的相关性，并确定PKD3促进肿瘤发展的信号机制。该项目的最终目标是评估PKD3作为前列腺癌新标记物和/或治疗靶点的价值。将获得有关前列腺癌发生机制的基本新知识，从而促进未来设计新的治疗策略，以限制或预防这种致命的疾病。