Targeting ATDC with PARP inhibitors in pancreatic cancer

使用 PARP 抑制剂靶向 ATDC 治疗胰腺癌

• 批准号: 7875693
• 负责人: MATS LJUNGMAN
• 金额: $ 16.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-13 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875693
• 关键词: Abbreviations; Applications Grants; Ataxia Telangiectasia; Biological Assay; Cell Proliferation; Cells; Clinical; Complement; Exhibits; Exposure to; Growth; Immunoprecipitation; Ionizing radiation; Laboratory mice; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; NOD/SCID mouse; Oncogenic; Outcome; PARP inhibition; Pathway interactions; Pharmaceutical Preparations; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Property; Propidium Diiodide; Proteins; Radiation; Radiation therapy; Radiosensitization; Reporting; Resistance; Role; Small Interfering RNA; TRIM Gene; TRIM Motif; ataxia telangiectasia mutated protein; attenuation; cancer cell; chemotherapy; drug mechanism; gemcitabine; inhibitor/antagonist; killings; new therapeutic target; overexpression; pancreas xenograft; pancreatic neoplasm; public health relevance; small hairpin RNA; therapeutic target; therapy resistant; tumor; tumor growth

DESCRIPTION (provided by applicant): We recently reported that ATDC (also known as TRIM29) is highly expressed in pancreatic cancers and that it exhibits oncogenic properties by promoting cell proliferation via the WNT/b-catenin pathway (Cancer Cell 15:207, 2009). Our preliminary results also show that ATDC protects pancreatic cancer cells against radiation and chemotherapy. The properties of growth promotion and resistance to therapy suggest that ATDC is an important therapeutic target. To better understand the function of ATDC and its role in resistance, we explored what proteins ATDC interacts with before and/or after exposure to ionizing radiation. Using immunoprecipitation assays we found that ATDC interacts with poly(ADP-ribose)polymerase1 (PARP1) and that this interaction is substantially increased following exposure to ionizing radiation. To investigate whether this interaction is dependent on the catalytic activity of PARP, we treated cells with PARP inhibitors and found surprisingly that this treatment lead to a marked loss of the cellular protein levels of ATDC. Furthermore, knockdown of Parp1 expression by siRNA resulted in reduced levels of ATDC indicating that PARP1 stimulates the expression of ATDC in pancreatic cancer cells. Importantly, our preliminary results suggest that PARP inhibition results in reduced proliferation and increased sensitivity to ionizing radiation of pancreatic cancer cells. We hypothesize that ATDC is a promising novel therapeutic target in pancreatic cancer because its inactivation may lead to both reduced tumor growth and sensitization to radiation therapy. Furthermore, we hypothesize that PARP inhibitors will target ATDC and selectively inhibit growth and sensitize ATDC-expressing pancreatic cancer tumors. PUBLIC HEALTH RELEVANCE: Pancreatic cancer has the worst outcome of any cancer and kills more than 30,000 people in the US annually. We recently found that the protein ATDC is expressed at abnormally high levels in pancreatic cancer and this overexpression promotes the growth and resistance of pancreatic tumors. Unexpectedly, we found that a class of chemotherapeutic drugs currently in clinical use reduces ATDC levels in pancreatic cancer cells and make them more sensitive to radiation. In this R21 proposal we will explore the mechanisms of how these drugs reduce ATDC levels and whether they will target ATDC in pancreatic tumors in laboratory mice.

描述（由申请人提供）：我们最近报道 ATDC（也称为 TRIM29）在胰腺癌中高度表达，并且它通过 WNT/b-连环蛋白途径促进细胞增殖而表现出致癌特性（Cancer Cell 15:207, 2009）。我们的初步结果还表明 ATDC 可以保护胰腺癌细胞免受放射和化疗的影响。促进生长和抵抗治疗的特性表明 ATDC 是一个重要的治疗靶点。为了更好地了解 ATDC 的功能及其在抵抗中的作用，我们探索了 ATDC 在暴露于电离辐射之前和/或之后与哪些蛋白质相互作用。使用免疫沉淀测定，我们发现 ATDC 与聚（ADP-核糖）聚合酶 1 (PARP1) 相互作用，并且这种相互作用在暴露于电离辐射后显着增加。为了研究这种相互作用是否依赖于 PARP 的催化活性，我们用 PARP 抑制剂处理细胞，并令人惊讶地发现这种处理导致 ATDC 细胞蛋白水平显着降低。此外，通过 siRNA 敲低 Parp1 表达导致 ATDC 水平降低，表明 PARP1 刺激胰腺癌细胞中 ATDC 的表达。重要的是，我们的初步结果表明，PARP 抑制会导致胰腺癌细胞的增殖减少并增加对电离辐射的敏感性。我们假设 ATDC 是胰腺癌的一个有前途的新型治疗靶点，因为它的失活可能会导致肿瘤生长减少和对放射治疗敏感。此外，我们假设 PARP 抑制剂将靶向 ATDC 并选择性抑制生长并使表达 ATDC 的胰腺癌肿瘤敏感。 公共健康相关性：胰腺癌是所有癌症中后果最严重的，每年在美国夺去 30,000 多人的生命。我们最近发现ATDC蛋白在胰腺癌中异常高水平表达，这种过度表达促进胰腺肿瘤的生长和抵抗。出乎意料的是，我们发现目前临床使用的一类化疗药物可以降低胰腺癌细胞中的ATDC水平，并使它们对辐射更加敏感。在这个 R21 提案中，我们将探讨这些药物如何降低 ATDC 水平的机制以及它们是否会针对实验室小鼠胰腺肿瘤中的 ATDC。