The role of PKD3 in prostate carcinogenesis

描述（由申请人提供）：本提案研究蛋白激酶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第二信使二酰基甘油（DAG）及其药理类似物磷酸酯的新靶点。DAG和phorbol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。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的渐进式核积累以及在人类前列腺肿瘤中的表达升高，揭示了PKD促进前列腺癌发展的潜在机制。PKD3促进前列腺癌细胞的生长、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信号位于PKC5的下游，PKC5是前列腺癌的一种致癌蛋白，并调节前列腺癌细胞中关键的细胞生长/存活调节通路，包括Akt和EKR1/2。这些发现支持了组成活性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作为一种新的生物标志物和前列腺癌治疗靶点的潜在价值。最终，可能会设计新的策略来靶向PKD3治疗前列腺癌以及其他DAG信号失调的疾病。本提案将检验三个具体目标：确定PKD3在体内前列腺癌发病机制中的作用。具体目标2。验证PKD3的核积累作为PKC5/PKD3组成活性的结果对前列腺癌细胞的生长、存活、迁移/侵袭至关重要的假设。具体目标3。确定PKD3与前列腺癌细胞获得性phorbol 12-肉豆酸13-醋酸酯（PMA）抗性和细胞增殖的相关性。

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.