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

• 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
• 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

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。