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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：
9391006
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 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9391006
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 Clinical Trials Complex Data Disseminated Malignant Neoplasm Doxycycline Engineering Epigenetic Process Epithelial Family Gene Targeting 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 Transcription Repressor/Corepressor Transforming Growth Factor beta Tumor Cell Line Tumor Cell Migration Virus Xenograft procedure base cancer cell cell motility chemotherapy design drug development 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.

这项研究旨在加深我们对细胞核 Bcl-xL 分子机制的理解。肿瘤转移。已知 B 细胞淋巴瘤 2 (Bcl-2) 家族蛋白在控制中发挥重要作用细胞凋亡和癌症失调。 Bcl-xL 是 Bcl-2 家族的抗凋亡成员之一，在各种癌细胞中经常过度表达。它控制细胞对细胞凋亡的承诺线粒体并防止细胞死亡。消除 Bcl-xL 以及其他抗细胞凋亡活性凋亡的 Bcl-2 成员作为癌症治疗的假定靶点受到了广泛的研究关注。使用基于禽病毒 RCASBP 的体内小鼠模型治疗胰腺神经内分泌肿瘤 (panNETs)，我们发现 Bcl-xL 的过度表达会刺激原发性 panNETs 的转移，而不会阻断细胞凋亡。我们发现 ABT-737（一种 Bcl-xL 的小分子抑制剂）不会损害 Bcl-xL 诱导的细胞迁移。我们证明 Bcl-xL 促进转移独立于其抗凋亡活性及其驻留在 panNET 细胞系和乳腺癌细胞系的线粒体中。我们证明了核- 靶向 Bcl-xL，而非线粒体 Bcl-xL 或核外 Bcl-xL，促进 EMT 和肿瘤细胞迁移。此外，Bcl-xL 增加 TGFβ1 启动子上的 H3K4me3，从而上调表达， TGFβ 中和抗体在体外阻断 Bcl-xL 的转移功能。根据我们的数据，我们假设 Bcl-xL 的转移功能主要归因于其核功能。为了检验这个假设，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、癌细胞系和人类小鼠模型癌症。癌细胞和小鼠模型的研究结果将被交叉检验，测试也将得到回报。从这项拟议研究中获得的信息预计将有助于建立以下机制： Bcl-xL 促进转移，同时为药物的进一步开发提供重要见解治疗性靶向 Bcl-xL 治疗转移性癌症。