The role of PKD3 in prostate carcinogenesis

PKD3在前列腺癌发生中的作用

• 批准号: 7816904
• 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/7816904
• 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）：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) 及其药理学类似物佛波酯的新靶标。 DAG 和佛波酯直接结合 PKD 的 C1 结构域，并通过蛋白激酶 C (PKC) 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 作为一种新型 DAG 靶点，对这些疾病具有重要的预后和治疗价值。我们研究的大量证据支持 PKD3（PKD 家族的新成员）在前列腺癌发生中的新作用。我们已经证明 PKD3 在人类前列腺肿瘤中进行性核积累以及表达升高，揭示了 PKD 促进前列腺癌发展的潜在机制。 PKD3 促进前列腺癌细胞生长、存活和迁移/侵袭，敲低 PKD3 抑制小鼠前列腺肿瘤异种移植物的生长。 PKD3 向 PKC5（前列腺癌中的一种致癌蛋白）下游发出信号，并调节关键的细胞生长/生存调控途径，包括前列腺癌细胞中的 Akt 和 EKR1/2。这些发现支持组成性活跃的 PKC5/PKD3 通路在前列腺肿瘤发生中的关键作用。拟议的研究将进一步剖析 PKD3 的信号传导机制，并确定其在前列腺癌发病机制中的功能影响。如果成功，这些研究将揭示 PKD3 作为前列腺癌新型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来靶向 PKD3 作为前列腺癌以及 DAG 信号传导失调的其他疾病的治疗方法。该提案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制中的作用。具体目标 2. 测试以下假设：由于 PKC5/PKD3 持续活跃，PKD3 的核积聚对于前列腺癌细胞的生长、存活、迁移/侵袭至关重要。具体目标 3. 确定 PKD3 在前列腺癌细胞中获得性佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 耐药性和细胞增殖中的相关性。公共健康相关性：PKD 家族作为二酰甘油的新靶标和 PKC 的效应物，可促进细胞生长和存活。 PKD 还与过度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前列腺癌的发展。这项研究将明确 PKD3 与前列腺癌发病机制的相关性，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。将获得有关前列腺肿瘤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疾病。