ATDC Function in Human Pancreatic Adenocarcinoma

ATDC 在人胰腺腺癌中的功能

• 批准号: 7920797
• 负责人: DIANE M SIMEONE
• 金额: $ 31.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920797
• 关键词: ATM gene; Adenocarcinoma; Apoptosis; Ataxia Telangiectasia; Cell Cycle Checkpoint; Cell Nucleus; DNA Damage; DNA Repair; Defect; Diagnosis; Disease; Genes; Genetic Transcription; Growth; Hereditary Disease; Human; In Vitro; Ionizing radiation; Lead; Link; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modality; Molecular; Neoplasm Metastasis; Nuclear; Pancreatic Adenocarcinoma; Pathway interactions; Patients; Protein Family; Proteins; Resistance; Role; Signal Pathway; Signal Transduction; Site; Stimulation of Cell Proliferation; Therapeutic; Tissues; Xenograft Model; base; beta catenin; cancer cell; chemotherapeutic agent; chemotherapy; gemcitabine; improved; in vivo; nanovector; new therapeutic target; novel; overexpression; pancreas xenograft; pancreatic neoplasm; pre-clinical; public health relevance; response; small hairpin RNA; therapy resistant; trafficking; tumor; tumor growth

DESCRIPTION (provided by applicant): Pancreatic cancer is a deadly disease characterized by late diagnosis, aggressive invasion of surrounding tissues, early metastasis, and resistance to therapy. There is an urgent need to develop highly effective, mechanism-based therapies to improve survival in these patients. We have recently found that the majority of human pancreatic adenocarcinomas specifically over-express the gene for Ataxia-Telangiectasia Group D Associated (ATDC). The ATDC gene was initially described in association with the genetic disorder ataxia-telangiectasia (AT) but was later found not to be the gene responsible for that disorder, and it's function remained unknown. We have identified ATDC as a novel DNA damage response gene that confers a survival advantage to pancreatic cancer cells when exposed to chemotherapy. We have shown that following DNA damage, ATDC traffics to the nucleus, is phosphorylated in response to gemcitabine and localizes to DNA repair foci. Loss of ATDC results in increased sensitivity to gemcitabine-induced apoptosis and a defect in downstream cell cycle checkpoint signaling. We have also found that high levels of ATDC confer a growth advantage to pancreatic cancer cells both in vitro and in vivo. The ATDC-mediated stimulation of cell proliferation may be due to enhancement of the beta-catenin pathway since overexpression of ATDC increases beta-catenin mediated transcription. We demonstrate that ATDC interacts with the HIT family protein HINT1, a negative regulator of the beta-catenin pathway, and we hypthesize that ATDC stimulates beta-catenin-mediated proliferation by sequestering HINT1. In this proposal, we will explore the following specific aims: 1) To examine the role of ATDC in the ATR-mediated DNA damage response. 2) To assess if ATDC's tumor promoting ability is linked to stimulation of the beta-catenin pathway through interactions with the HIT1 family protein HINT1. 3) To analyze the efficacy of targeting ATDC as a therapeutic modality in a pre-clinical, primary human pancreatic cancer orthotopic xenograft model. PUBLIC HEALTH RELEVANCE: We propose that ATDC is a promising novel therapeutic target in pancreatic cancer because it's inactivation may lead to both reduced tumor growth and sensitization to chemotherapy.

描述（由申请人提供）：胰腺癌是一种致命的疾病，其特征是诊断较晚，侵袭周围组织，早期转移和治疗抵抗。迫切需要开发高效的、基于机制的治疗方法来提高这些患者的生存率。我们最近发现，大多数人胰腺癌特异性过表达共济失调-毛细血管扩张D组相关（ATDC）基因。ATDC基因最初被描述为与遗传性疾病共济失调-毛细血管扩张症（AT）相关，但后来发现不是导致该疾病的基因，其功能仍然未知。我们已经确定ATDC作为一种新的DNA损伤反应基因，赋予胰腺癌细胞暴露于化疗时的生存优势。我们已经表明，在DNA损伤后，ATDC运输到细胞核，响应于吉西他滨被磷酸化并定位于DNA修复灶。ATDC的缺失导致对吉西他滨诱导的细胞凋亡的敏感性增加和下游细胞周期检查点信号传导的缺陷。我们还发现，高水平的ATDC在体外和体内都赋予胰腺癌细胞生长优势。ATDC介导的细胞增殖刺激可能是由于β-连环蛋白途径的增强，因为ATDC的过表达增加了β-连环蛋白介导的转录。我们证明了ATDC与HIT家族蛋白HINT 1（β-连环蛋白通路的负调节因子）相互作用，我们推测ATDC通过隔离HINT 1刺激β-连环蛋白介导的增殖。本研究的主要目的是：1）研究ATDC在ATR介导的DNA损伤反应中的作用。2)评估ATDC的肿瘤促进能力是否与通过与HIT 1家族蛋白HINT 1相互作用刺激β-连环蛋白通路有关。3)在临床前原发性人胰腺癌原位异种移植模型中分析靶向ATDC作为治疗方式的疗效。公共卫生相关性：我们认为ATDC是胰腺癌治疗的一个有前途的新靶点，因为它的失活可能导致肿瘤生长减少和对化疗敏感。