Effect of Protein Kinase D1(PKD1)- E-Cadherin Interaction in Prostate Cancer

描述(由申请人提供)： 对于患有前列腺癌的退伍军人来说，进展到去势抵抗是致命的。退伍军人管理局合作小组的研究证实，雄激素消融是退伍军人晚期前列腺癌的有效姑息治疗。大多数晚期前列腺癌患者的治疗都集中在雄激素受体(AR)信号转导上，由于癌细胞对极低的组织雄激素水平具有极高的敏感性，雄激素受体信号在前列腺癌的去势抵抗中继续发挥重要作用。晚期前列腺癌的新疗法，包括多西他赛化疗和西普鲁尔-T癌症疫苗，可提高约2-4个月的存活率，这突显了显著提高转移性前列腺癌患者存活率的必要性。我们建议研究前列腺癌AR信号的一种新的调节机制，这将为开发生物标记物和治疗靶点提供新的机会。蛋白激酶D_1(PKD_1)是一种新的前列腺癌肿瘤和转移抑制因子，它与主要的细胞黏附蛋白E-钙粘附素相互作用，调节前列腺癌的细胞增殖、侵袭和迁移。通过与E-钙粘蛋白和底物磷酸化的相互作用，PKD-1影响AR的主要辅助激活剂--β-连环蛋白的亚细胞定位和转录功能。在这项计划中，我们将利用最先进的分子和细胞生物学技术和转基因小鼠模型，研究PKD1和E-钙粘素相互作用和失调在前列腺癌进展中的作用以及β-连环蛋白在AR共激活中的变化。在前列腺癌中建立调节AR活性的新的信号通路将为发现新的生物标志物和影响去势抵抗前列腺癌的AR功能提供更多的机会。

DESCRIPTION (provided by applicant): Progression to castration resistance is lethal in veterans with prostate cancer. Seminal Veterans Administration cooperative group studies established androgen ablation as effective palliative treatment for veterans with advanced prostate cancer. Most treatments for patients with advanced prostate cancer is centered on androgen receptor (AR) signaling, which continues to play a major role through castration resistance in prostate cancer because exquisite sensitivity of cancer cells to extremely low levels of tissue androgens. Newer treatments for advanced prostate cancer including Docetaxol chemotherapy and Sipuleucel-T cancer vaccine produce improvement in survival of about 2-4 months, highlighting need for dramatic improvement in survival for patients with metastatic prostate cancer. We propose to investigate a novel regulatory mechanism of AR signaling in prostate cancer that will provide newer opportunities to develop biomarkers and therapeutic targets. Protein Kinase D1 (PKD1) is a novel tumor and metastasis suppressor in prostate cancer that interacts with E-cadherin, a major cell adhesion protein, to regulate cell proliferation, invasion and migration in prostate cancer. Through interaction with E-cadherin and substrate phosphorylation, PKD 1 influences subcellular localization and transcriptional function of beta-catenin, a major co-activator of AR. In this proposal, we will investigate the effect to PKD1 and E-cadherin interaction and dysregulation on prostate cancer progression and alteration in AR co activation by beta-catenin using state of the art molecular and cell biological techniques and transgenic mouse models. Establishing novel signaling pathway that regulates AR activity in prostate cancer will provide additional opportunities to identify new biomarkers and influence AR function in castration resistant prostate cancer.