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Role of DDB2 in chemotherapeutic agents-induced apoptosis and platinum resistance

DDB2 在化疗药物诱导的细胞凋亡和铂类耐药中的作用

基本信息

批准号：
8711333
负责人：
Qien Wang
金额：
$ 24.56万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711333
关键词：
Address Apoptosis Apoptotic BCL2 gene Binding Biochemical Biological Assay Cancer cell line Cell Line Cell-Free System Cells Cisplatin Clinical Commit DNA Damage DNA-Binding Proteins Development Event Exhibits Flow Cytometry Gene Proteins Genetic Transcription Human Immunoprecipitation Knowledge Laboratories Luciferases Malignant Neoplasms Malignant neoplasm of ovary Measures Mediating Mismatch Repair Molecular Mus Mutate Names Patients Pharmaceutical Preparations Platinum Proteins Reporting Research Resistance Reverse Transcriptase Polymerase Chain Reaction Role Sampling Severe Combined Immunodeficiency Signal Transduction Solid Neoplasm Suicide Technology Testing Time Tissues Transfection Translating Tumor Tissue Tumor-Derived Western Blotting Work antitumor agent base cancer cell cell injury chemotherapeutic agent chromatin immunoprecipitation cytotoxicity design improved in vivo killings knock-down neoplastic neoplastic cell overexpression pro-apoptotic protein promoter protein protein interaction tumor

项目摘要

DESCRIPTION (provided by applicant): Cisplatin is one of the most potent anti-tumor agents, which displays clinical activity against a wide variety of solid tumors. The anti-neoplastic activity of cisplatin results from cisplatin- induced DNA damage, which further triggers cellular apoptosis. However, the effective use of cisplatin is limited by the development of cisplatin resistance in cancer cells. Damaged DNA binding protein (DDB2) has been reported to be able to bind UV- or cisplatin-induced DNA damage, and believed to have a correlation with the apoptotic event, especially the apoptosis induced by DNA damaging agents. However, the relationship between DDB2 and cisplatin- induced apoptosis needs to be validated and the mechanism needs to be explored. The specific hypothesis addressed in this proposal is that DDB2 mediates cisplatin-induced apoptosis through binding DNA damage to relay the apoptotic signals, and regulating pro- and anti-apoptotic proteins; as a result, DDB2 deficiency confers cancer cells resistance to cisplatin. The proposed work will utilize relevant biochemical, biophysical, immunological, cellular and molecular technologies mostly established and ongoing in the PI's laboratory to address the following specific aims: (1) To validate the role of DDB2 in cisplatin-induced apoptosis and the relationship between DDB2 and Bcl-2 in varying cancer cell lines and human tumor tissues; (2) To define the role of DDB2 recognition of cisplatin-induced DNA damage in triggering apoptosis; (3) To delineate the mechanism through which DDB2 down-regulates Bcl-2 level; (4) To reveal the relationship between DDB2 and p53 in the cisplatin-induced apoptosis; (5) To test the role of DDB2 in cisplatin sensitivity and cisplatin- induced apoptosis in vivo. The experimental focus of this proposal is on the relationship between DDB2 and apoptosis. Thus, the above-mentioned specific aims are designed to provide a comprehensive assessment of the regulatory function of DDB2 on cisplatin-induced apoptosis and the development of cisplatin resistance.

描述（由申请人提供）：顺铂是最有效的抗肿瘤药物之一，对多种实体瘤显示出临床活性。顺铂的抗肿瘤活性源于顺铂诱导的DNA损伤，其进一步触发细胞凋亡。然而，顺铂的有效使用受到癌细胞中顺铂耐药性的发展的限制。损伤的DNA结合蛋白（DDB 2）被认为能与紫外线或顺铂诱导的DNA损伤结合，并被认为与细胞凋亡相关，尤其是与DNA损伤剂诱导的细胞凋亡相关。然而，DDB 2与顺铂诱导的细胞凋亡之间的关系需要验证，其机制需要探索。该提案中提出的具体假设是，DDB 2通过结合DNA损伤以传递凋亡信号并调节促凋亡蛋白和抗凋亡蛋白来介导顺铂诱导的凋亡;因此，DDB 2缺陷赋予癌细胞对顺铂的抗性。拟开展的工作将利用主要在PI实验室建立和正在进行的相关生物化学、生物物理学、免疫学、细胞和分子技术，以解决以下具体目标：（1）验证DDB 2在顺铂诱导的细胞凋亡中的作用以及DDB 2和Bcl-2在不同癌细胞系和人类肿瘤组织中的关系;（2）探讨DDB 2识别顺铂诱导的DNA损伤在细胞凋亡中的作用，（3）DDB 2下调Bcl-2表达的机制，（4）DDB 2与p53在顺铂诱导的细胞凋亡中的关系，（5）DDB 2与p53在顺铂诱导的细胞凋亡中的作用，（6）DDB 2与p53的关系。（5）检测DDB 2在体内顺铂敏感性和顺铂诱导的细胞凋亡中的作用。该建议的实验重点是DDB 2和细胞凋亡之间的关系。因此，上述具体目的旨在提供DDB 2对顺铂诱导的细胞凋亡和顺铂耐药性发展的调节功能的综合评估。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DDB2 increases radioresistance of NSCLC cells by enhancing DNA damage responses.

DOI：
10.1007/s13277-016-5203-y
发表时间：
2016-10
期刊：
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
影响因子：
0
作者：
Zou N;Xie G;Cui T;Srivastava AK;Qu M;Yang L;Wei S;Zheng Y;Wang QE
通讯作者：
Wang QE

miR-93 promotes TGF-β-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells.

DOI：
10.1007/s13277-015-4328-8
发表时间：
2016-04
期刊：
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
影响因子：
0
作者：
Qu MH;Han C;Srivastava AK;Cui T;Zou N;Gao ZQ;Wang QE
通讯作者：
Wang QE

XPC inhibits NSCLC cell proliferation and migration by enhancing E-Cadherin expression.