Function and Regulation Mechanisms of Polo-like Kinase 3 in Pancreatic Cancer

Polo样激酶3在胰腺癌中的功能及调控机制

基本信息

批准号：
8029562
负责人：
PAUL J CHIAO
金额：
$ 31.8万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8029562
关键词：
1p32 Adult Apoptosis Architecture Arginine Binding Biochemical Biological C-terminal Cancer cell line Cancer-Predisposing Gene Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell Line Cell division Cells Chromosomes Cleaved cell Cytokine-Inducible Kinase DNA Damage DNA damage checkpoint Data Development Diagnosis Disease Down-Regulation Ductal Elderly Endopeptidases Epithelial Foundations G2/M Arrest Genomic Instability Goals Human In Vitro Knockout Mice Lead Left Ligands Liposome-Mediated Gene Transfer Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Mediating Mitosis Mitotic Modeling Molecular Molecular Target Mus Mutant Strains Mice Mutate Mutation Normal tissue morphology Nucleic Acid Regulatory Sequences Organ Pancreas Pancreatic Adenocarcinoma Patients Phosphatidylinositols Phosphorylation Phosphotransferases Physiological Play Polo-Box Domain Protein-Serine-Threonine Kinases Proteins Regulation Research Research Personnel Resistance Role S Phase Signal Pathway Signal Transduction Site Survival Rate Testing Tissues Tumor Suppressor Proteins United States Work Xenograft procedure anticancer research base cancer cell cancer type effective therapy genetic profiling human PLK1 protein improved in vivo insight mortality mouse model mutant novel overexpression pancreatic cancer cells pancreatic neoplasm phosphatidylinositol 3,4,5-triphosphate public health relevance research study response tripolyphosphate tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer poses one of the greatest challenges in cancer research. Pancreatic adenocarcinoma is the fourth-leading cause of adult cancer mortality in the United States. The five-year survival rate remains at 1-3%, and the median survival duration after diagnosis is less than six months. Pancreatic cancer is characterized by locally advanced or metastatic disease and lack of response to current therapies. Based on the most frequently detected mutations in this disease, a genetic profile for pancreatic cancer is emerging. The expression of polo-like kinase 3 (Plk3), one of the four mammalian polo-like kinases, is significantly decreased in nearly 70% of human pancreatic cancer tissues and in most pancreatic cancer cell lines. Furthermore, Plk3 localizes to chromosome 1p32, a locus thought to contain cancer susceptibility genes. Recently, Plk3-knockout mice were generated and these mice developed tumors in various organs at advanced age. Plk3 is a multi-functional protein that plays critical roles in the regulation of apoptosis and responses to DNA damage. Expression of Plk3 induced apoptosis in pancreatic cancer cells in cell culture and inhibited pancreatic tumor growth by liposome- mediated gene transfer in a xenograft mouse model. These findings demonstrate that Plk3 functions as a tumor suppressor and plays an essential role in pancreatic cancer cell apoptosis. However, the underlying molecular mechanism through which Plk3 is regulated remains elusive. The long-term goal of our research is to develop more effective therapies for patients with pancreatic cancer. On the basis of our preliminary results, we hypothesize that loss of Plk3 expression plays an essential role in the development of pancreatic cancer and that Plk3 activation is an essential regulation that integrates signals that control genomic instability through inducible phosphorylation and/or interaction with adaptor molecules. To test our hypotheses, three specific aims were proposed: (1) demonstrate the role of Plk3 in the development of pancreatic cancer; (2) determine the expression of Plk3 is silenced in pancreatic cancer and role of Plk3 in the control of cell division and DNA damage checkpoints; (3) identify the mechanisms by which activation of Plk3 is regulated. The findings from our proposed study will provide insight into the mechanisms of Plk3 regulation and the essential role of Plk3 as a tumor suppressor in pancreatic cancer. Importantly, this study may discover novel molecular targets that could lead to more effective treatments for pancreatic cancer. PUBLIC HEALTH RELEVANCE: This project is aimed at elucidating the tumor suppressor function of Plk3 in pancreatic tumor development and determining the novel mechanism by which Plk3 is silenced and regulated. We hypothesize that down regulation of Plk3 plays an essential role in development of pancreatic cancer and activation of Plk3 by proteolytic cleavage is regulated by PI3K. We will test our hypothesis by three specific aims using a combination of Plk3 knockout mouse models and Plk3 knockdown cell lines with biochemical and cell biological approaches, to fill in the gaps in our understanding of the novel molecular mechanisms of Plk3 regulation and role of Plk3 in tumorigenesis of pancreas.

描述（由申请人提供）：胰腺癌是癌症研究中最大的挑战之一。胰腺腺癌是美国成人癌症死亡率的第四个主要原因。五年生存率保持在1-3％，诊断后的中位存活时间少于六个月。胰腺癌的特征是局部晚期或转移性疾病以及对当前疗法的反应。基于该疾病中最常见的突变，胰腺癌的遗传特征正在出现。在近70％的人类胰腺癌组织和大多数胰腺癌细胞系中，polo样激酶3（PLK3）的表达显着降低。此外，PLK3本地化为1p32染色体，这是一个被认为包含癌症基因的基因座。最近，产生了PLK3敲除小鼠，这些小鼠在高龄在各种器官中出现肿瘤。 PLK3是一种多功能蛋白，在调节细胞凋亡和对DNA损伤的反应中起着关键作用。 PLK3在细胞培养中诱导胰腺癌细胞中凋亡的凋亡，并通过脂质体介导的基因转移抑制胰腺肿瘤的生长。这些发现表明，PLK3是肿瘤抑制因子，在胰腺癌细胞凋亡中起着至关重要的作用。但是，通过调节PLK3的基本分子机制仍然难以捉摸。我们研究的长期目标是为胰腺癌患者开发更有效的疗法。根据我们的初步结果，我们假设PLK3表达的丧失在胰腺癌的发展中起着至关重要的作用，并且PLK3激活是一种重要的调节，它整合了通过诱导磷酸化和/或与衔接子分子相互作用来控制基因组不稳定性的信号。为了检验我们的假设，提出了三个具体目标：（1）证明PLK3在胰腺癌发展中的作用；（2）确定胰腺癌中PLK3的表达是沉默的，以及PLK3在控制细胞分裂和DNA损伤检查点中的作用；（3）确定调节PLK3激活的机制。我们提出的研究的发现将洞悉PLK3调节机制以及PLK3作为胰腺癌中肿瘤抑制剂的重要作用。重要的是，这项研究可能会发现新的分子靶标，这些靶标可能会导致对胰腺癌的更有效治疗。公共卫生相关性：该项目旨在阐明PLK3在胰腺肿瘤发育中的肿瘤抑制功能，并确定PLK3沉默和调节的新型机制。我们假设下调PLK3的下调在胰腺癌的发展中起着至关重要的作用，而PI3K调节了蛋白水解裂解的PLK3。我们将使用PLK3基因敲除小鼠模型和PLK3敲低细胞系与生化和细胞生物学方法的组合来检验我们的假设，以填补我们对PLK3调节的新分子机制和PLK3在PLK3中的新分子机制的差距胰腺的肿瘤发生。