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Beyond apoptosis, Bcl-xL in tumor metastasis

除了细胞凋亡之外，Bcl-xL 在肿瘤转移中的作用

基本信息

批准号：
10056197
负责人：
Yi-Chieh Nancy Du
金额：
$ 39.07万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056197
关键词：
Apoptosis Apoptosis Regulation Gene Apoptotic Attention BCL2 gene Binding Birds Blocking Antibodies Breast Cancer cell line CTBP2 gene Cancer Survivor Cancer cell line Cell Death Cell Nucleus Cell model Cells ChIP-seq Chemoresistance Chemotherapy and/or radiation Clinical Trials Complex Data Disseminated Malignant Neoplasm Doxycycline Engineering Epigenetic Process Epithelial Family Gene Chips Genes Genetic Transcription Genetically Engineered Mouse Goals Growth Histones Human In Vitro Islet Cell Tumor Knock-out MLL gene Maintenance Malignant Neoplasms Maps Mediating Methyltransferase Mitochondria Molecular Neoplasm Metastasis Nuclear Nuclear Translocation Patients Play Protein Family Publishing Radiation Radiation therapy Reporting Research Residual Tumors Resistance Role Scheme Signal Transduction Specimen System Testing Therapeutic Transforming Growth Factor beta Tumor Cell Line Tumor Cell Migration Virus Xenograft procedure base cancer cell cell motility design drug development genetic corepressor human cancer mouse model in vivo inhibitor/antagonist insight member migration mouse model mutant mutant mouse model neoplastic cell neutralizing antibody novel overexpression prevent promoter prototype reconstitution recruit residence small hairpin RNA small molecular inhibitor small molecule inhibitor targeted cancer therapy therapeutic target tumor tumor growth tumor progression

项目摘要

This proposed study is to advance our understanding of the molecular mechanism of nuclear Bcl-xL in tumor metastasis. B cell lymphoma 2 (Bcl-2) family proteins are known to play an important role in the control of apoptosis and the dysregulation in cancer. Bcl-xL is one of the anti-apoptotic members of the Bcl-2 family, frequently overexpressed in various cancer cells. It controls cellular commitment to apoptosis at the mitochondria and prevents cell death. Abrogating the anti-apoptotic activity of Bcl-xL as well as other anti- apoptotic Bcl-2 members as a putative target of cancer therapy has received significant research attention. Using an avian virus RCASBP-based in vivo mouse model for pancreatic neuroendocrine tumors (panNETs), we found that overexpression of Bcl-xL stimulates metastasis of primary panNETs without blocking apoptosis. We showed that ABT-737, a small molecular inhibitor of Bcl-xL, does not impair Bcl-xL-induced cell migration. We demonstrated that Bcl-xL promotes metastasis independent of its anti-apoptotic activity and its residence at the mitochondria in panNET cell lines as well as breast cancer cell line. We showed that nuclear- targeted Bcl-xL, not mitochondrial Bcl-xL nor Bcl-xL outside the nucleus, promotes EMT and tumor cell migration. Furthermore, Bcl-xL increases H3K4me3 on the promoter of TGFβ1 to upregulate the expression, and TGFβ neutralizing antibodies block the metastatic function of Bcl-xL in vitro. Based on our data, we hypothesize that the metastatic function of Bcl-xL is attributed primarily to its nuclear function. To test this hypothesis, we will use multiple experimental systems, which include Bcl-xL mutants, Bcl-xL knockout, doxycycline-inducible overexpression and shRNA, cancer cell lines, and mouse models for human cancer. The findings from cancer cells and mouse models will be cross-examined and the tests reciprocated. Information derived from this proposed study is expected to be useful in establishing the mechanisms by which Bcl-xL promotes metastasis, while providing significant insights into further development of drugs therapeutically targeting Bcl-xL in the treatment of metastatic cancers.

这项研究旨在进一步了解核Bcl-xL在细胞凋亡中的分子机制。肿瘤转移已知B细胞淋巴瘤2（Bcl-2）家族蛋白质在控制淋巴瘤中起重要作用。细胞凋亡和失调。Bcl-xL是Bcl-2家族的抗凋亡成员之一，在多种癌细胞中频繁过度表达。它控制细胞在凋亡发生时的细胞定向。线粒体并防止细胞死亡。消除Bcl-xL以及其他抗凋亡药物的抗凋亡活性，凋亡的Bcl-2成员作为肿瘤治疗的假定靶点已受到显著的研究关注。使用基于禽病毒RCASBP的胰腺神经内分泌肿瘤体内小鼠模型我们发现，Bcl-xL的过表达刺激原发性panNET的转移，而不阻断凋亡我们发现Bcl-xL的小分子抑制剂ABT-737不损害Bcl-xL诱导的细胞，迁移我们证明Bcl-xL促进转移不依赖于其抗凋亡活性和其抗肿瘤活性。在panNET细胞系以及乳腺癌细胞系中，我们发现核武器- 靶向Bcl-xL，而不是线粒体Bcl-xL或核外Bcl-xL，促进EMT和肿瘤细胞迁移此外，Bcl-xL通过增加TGFβ1启动子上的H3 K4 me 3来上调表达， TGFβ中和抗体在体外阻断Bcl-xL的转移功能。根据我们的数据，假设Bcl-xL的转移功能主要归因于其核功能。为了验证这一假设，我们将使用多个实验系统，其中包括Bcl-xL突变体，Bcl-xL 敲除、多西环素诱导的过表达和shRNA、癌细胞系和用于人类肿瘤的小鼠模型癌来自癌细胞和小鼠模型的发现将被交叉检查，并且测试将相互进行。从这项拟议的研究中获得的信息预计将有助于建立机制， Bcl-xL促进转移，同时为药物的进一步开发提供重要见解在转移性癌症的治疗中治疗性靶向Bcl-xL。