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

描述（由申请人提供）： 前列腺癌退伍军人进展到去势抵抗是致命的。美国退伍军人管理局合作组研究确定雄激素消融是晚期前列腺癌退伍军人的有效姑息治疗。晚期前列腺癌患者的大多数治疗方法都以雄激素受体（AR）信号传导为中心，由于癌细胞对极低水平的组织雄激素具有极高的敏感性，因此AR信号传导通过前列腺癌的去势抵抗继续发挥主要作用。晚期前列腺癌的较新治疗方法，包括多西他赛化疗和Sipuleucel-T癌症疫苗，可使生存期延长约2-4个月，突出表明需要显著改善转移性前列腺癌患者的生存期。我们建议研究前列腺癌中AR信号的新调控机制，这将为开发生物标志物和治疗靶点提供新的机会。蛋白激酶D1（Protein Kinase D1，PKD 1）是一种新型的前列腺癌肿瘤和转移抑制因子，与主要的细胞粘附蛋白E-钙粘蛋白相互作用，调节前列腺癌细胞的增殖、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的主要共激活因子β-连环蛋白的亚细胞定位和转录功能。在这个提议中，我们将使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PKD 1和E-钙粘蛋白相互作用和失调对前列腺癌进展和β-连环蛋白AR共激活的改变的影响。建立调节前列腺癌中AR活性的新型信号通路将为鉴定新的生物标志物和影响去势抵抗性前列腺癌中的AR功能提供额外的机会。

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.