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

• 批准号: 8445298
• 负责人: PAUL J CHIAO
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/8445298
• 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; research study; response; tripolyphosphate; tumor; tumor growth; tumorigenesis

Project Summary 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.

项目摘要 胰腺癌是癌症研究中最大的挑战之一。胰 腺癌是美国成人癌症死亡率的第四个主要原因。这 五年生存率保持在1-3％，诊断后的中位生存时间较少 超过六个月。胰腺癌的特征是局部晚期或转移性疾病 并且缺乏对当前疗法的反应。基于最常见的突变 这种疾病是胰腺癌的遗传特征。类似polo的表达 激酶3（PLK3）是四个哺乳动物类球激酶之一，几乎显着降低 70％的人胰腺癌组织和大多数胰腺癌细胞系。此外， PLK3定位于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，这些小鼠在各种 高龄的器官。 PLK3是一种多功能蛋白，在 调节细胞凋亡和对DNA损伤的反应。 PLK3诱导凋亡的表达 在胰腺癌细胞中的细胞培养中，并通过脂质体抑制胰腺肿瘤生长 异种移植小鼠模型中介导的基因转移。这些发现表明PLK3 充当肿瘤抑制剂，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患者开发更有效的疗法 胰腺癌。根据我们的初步结果，我们假设PLK3的丢失 表达在胰腺癌的发展中起着至关重要的作用 激活是一个基于控制基因组不稳定性的信号的基本调节 通过诱导的磷酸化和/或与衔接分子的相互作用。测试我们的 假设提出了三个具体目标：（1）证明PLK3在 胰腺癌的发展； （2）确定PLK3的表达在胰腺中被沉默 PLK3在控制细胞分裂和DNA损伤检查点的癌症和作用； （3）识别 调节PLK3激活的机制。我们提议的研究的发现 将洞悉PLK3调节的机制以及PLK3作为一个的基本作用 胰腺癌中的肿瘤抑制剂。重要的是，这项研究可能会发现新的分子 可能导致胰腺癌更有效治疗的靶标。