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: 8061692
• 负责人: MATS LJUNGMAN
• 金额: $ 19.33万
• 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/8061692
• 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 cancer cells; 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(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，并通过WNT/b-catenin途径促进细胞增殖而显示出致癌特性(癌细胞15：207,2009)。我们的初步结果还表明，ATDC对胰腺癌细胞具有保护作用，使其免受放射和化疗的影响。ATDC具有促进生长和抵抗治疗的特性，是一种重要的治疗靶点。为了更好地了解ATDC的功能及其在抗性中的作用，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。利用免疫沉淀实验，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著增加。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，令人惊讶的是，这种处理导致ATDC的细胞蛋白水平显著下降。此外，siRNA下调PARP1的表达导致ATDC的表达水平降低，表明PARP1刺激胰腺癌细胞ATDC的表达。重要的是，我们的初步结果表明，抑制PARP导致胰腺癌细胞增殖减少，对电离辐射的敏感性增加。我们假设ATDC是一种很有前途的胰腺癌新的治疗靶点，因为它的失活可能会导致肿瘤生长减少和对放射治疗的增敏。此外，我们假设PARP抑制剂将以ATDC为靶点，选择性地抑制表达ATDC的胰腺癌肿瘤的生长和增敏。 与公共健康相关：胰腺癌是所有癌症中预后最差的，每年在美国导致超过3万人死亡。我们最近发现，ATDC蛋白在胰腺癌中异常高水平表达，这种过度表达促进了胰腺肿瘤的生长和耐药。出乎意料的是，我们发现目前临床使用的一类化疗药物降低了胰腺癌细胞中ATDC的水平，并使其对辐射更敏感。在这份R21提案中，我们将探索这些药物如何降低ATDC水平的机制，以及它们是否针对实验室小鼠胰腺肿瘤中的ATDC。