Regulation of Rap1 Prenylation and Trafficking in Breast Cancer

乳腺癌中 Rap1 异戊二烯化和贩运的调控

基本信息

批准号：
9026584
负责人：
Carol Lucille Williams
金额：
$ 35.17万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9026584
关键词：
4T1 Adenosine A2B Receptor Adherens Junction Affect Agonist Animal Model Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis C-terminal Cadherins Cell Nucleus Cell membrane Cell-Cell Adhesion Cells Clinic Clinical Clinical Trials Cyclic AMP-Dependent Protein Kinases Disease Drug Targeting Drug usage Endocytosis Event Exhibits FDA approved G-Protein-Coupled Receptors Goals Health Human Immunocompetent Immunodeficient Mouse MCF7 cell MDA MB 231 Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mediating Membrane Membrane Protein Traffic Metastatic breast cancer Modeling Molecular Chaperones Molecular Profiling Monomeric GTP-Binding Proteins Neoplasm Metastasis Nuclear Nuclear Translocation Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Proteins RNA Interference Rattus Receptor Activation Regulation Reporting Research Signal Pathway Signal Transduction Staging Testing Tissue Microarray Tumor Subtype Xenograft procedure autocrine base beta catenin beta-adrenergic receptor dimethylbenzanthracene drug testing innovation interest isoprenoid malignant breast neoplasm malignant phenotype mutant neoplastic cell novel novel strategies novel therapeutic intervention paracrine prenylation receptor receptor expression receptor-mediated signaling trafficking tumor tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The proposed research will explore a new approach to diminish breast cancer metastasis by targeting G protein-coupled receptors (GPCRs) that control the prenylation of the small GTPase Rap1B. Prenylated Rap1B localizes at the plasma membrane of breast cancer cells and stabilizes adherens junctions, which promotes cell-cell adhesion and diminishes the release of metastatic cells from breast tumors. We recently discovered that Rap1B prenylation is suppressed by activating adenosine A2B receptors (A2BR) on breast cancer cells. We reported that A2BR activation causes protein kinase A to phosphorylate newly synthesized Rap1B, which decreases the interaction of Rap1B with the chaperone protein SmgGDS and prohibits Rap1B from entering the prenylation pathway. These events promote the cytosolic and nuclear accumulation of non-prenylated Rap1B, resulting in loss of cell-cell adhesion and acquisition of a metastatic phenotype. This GPCR-mediated pathway that promotes the metastatic phenotype is very novel, because it was previously thought that cells do not possess signaling mechanisms to suppress prenylation, and it was thought that suppressing the prenylation of small GTPases would inhibit, rather than promote, metastasis. Based on our discovery, inactivating A2BR should restore Rap1B prenylation and trafficking to the cell membrane, which will increase cell- cell adhesion and diminish the release of metastatic cells from the tumor. We recently discovered that other GPCRs (in addition to A2BR) can suppress Rap1B prenylation in breast cancer cells. These GPCRs are inactivated by drugs that are currently being given to patients with diseases other than cancer. We hypothesize that these drugs can be used to inactivate the GPCRs that suppress the prenylation of Rap1B in breast cancer cells, resulting in increased Rap1B prenylation, increased cell-cell adhesion, and diminished metastasis. This hypothesis will be tested by 1) identifying GPCRs that promote the metastatic phenotype of cultured breast cancer cells by suppressing the prenylation and membrane trafficking of Rap1B, 2) testing drugs that inactivate these GPCRs, to determine if they will diminish breast cancer metastasis in animal models by restoring normal Rap1B prenylation in the tumor cells, and 3) examining patients' breast tumors to determine if expression of specific GPCRs and diminished Rap1B prenylation are associated with specific tumor subtypes and a more aggressive stage. Accomplishing these goals will provide significant benefits by developing an innovative strategy to inhibit breast cancer metastasis.

描述（由适用提供）：拟议的研究将通过靶向控制小型GTPase RAP1B的原化的G蛋白偶联受体（GPCR）来探索一种新方法来减少乳腺癌转移。特定的RAP1B定位于乳腺癌细胞的质膜并稳定粘附连接，从而促进细胞细胞粘合剂并减少从乳腺肿瘤中释放转移性细胞。我们最近发现，Rap1b促苯抑制通过激活乳腺癌细胞上的腺苷A2B受体（A2BR）。我们报道了A2BR激活会导致蛋白激酶A磷酸化新合成的RAP1B，从而降低了RAP1B与伴侣蛋白蛋白SMGGDS的相互作用，并禁止RAP1B进入蛋白酶化途径。这些事件促进了非丙二醇化RAP1B的胞质和核积累，从而导致细胞 - 细胞粘附的丧失和转移表型的获得。这种促进转移性表型的GPCR介导的途径非常新颖，因为以前认为细胞没有信号传导机制来抑制前烯基化，并且人们认为抑制小GTPases的原始化可以抑制，而不是促进转移。基于我们的发现，灭活A2BR应恢复RAP1B的原始化并运输到细胞膜，这将增加细胞 - 细胞粘合剂并减少从肿瘤中转移细胞的释放。我们最近发现，其他GPCR（除了A2BR之外）还可以抑制乳腺癌细胞中RAP1B的前化。这些GPCR被目前正在为癌症以外的疾病患者提供的药物灭活。我们假设这些药物可用于使抑制乳腺癌细胞中Rap1b的前化的GPCR灭活，从而导致RAP1B蛋白酶升高，细胞 - 细胞粘附性升高和转移减少。 This hypothesis will be tested by 1) identifying GPCRs that promote the metastatic phenotype of cultured breast cancer cells by suppressing the prenylation and membrane trafficking of Rap1B, 2) testing drugs that inactivate these GPCRs, to determine if they will diminish breast cancer metastasis in animal models by restoring normal Rap1B prenylation in the tumor cells, and 3) examining patients' breast tumors to determine if expression特定的GPCR和RAP1B序列化降低与特定的肿瘤亚型和更具侵略性的阶段有关。实现这些目标将通过制定创新的策略来抑制乳腺癌转移，从而为您带来重大好处。