Understanding role of O-GlcNAcylation on cancer cell metabolism and survival

了解 O-GlcNAc 酰化对癌细胞代谢和存活的作用

基本信息

批准号：
8651577
负责人：
Christina Ferrer
金额：
$ 4.17万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2016-09-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651577
关键词：
Address Aerobic Affect American Apoptosis Apoptotic Attenuated BCL2 gene Biology Breast Cancer Cell Breast Cancer Model Cancer Cell Growth Cancer Etiology Cancer Patient Cell Cycle Arrest Cell Death Cell Survival Cells Cessation of life Complex Data Deoxyglucose Dependency Development Endoplasmic Reticulum Enzymes Epithelial Cells Exhibits Family Foundations Glucose Glycolysis Goals Growth Heat shock proteins Hexosamines Hypoxia In Vitro Link Malignant Neoplasms Mammalian Cell Mammary gland Mass Spectrum Analysis Mediating Mediator of activation protein Metabolic Metabolic Pathway Metabolic stress Metabolism Mitotic Modification Molecular Molecular Target Nuclear Nutrient O-GlcNAc transferase Oncogenic Output Oxygen Pathway interactions Patients Pattern Phenotype Play Post-Translational Protein Processing Primary Neoplasm Process Production Protein Dynamics Proteins RNA Interference Recruitment Activity Regulation Role Second Primary Cancers Serine Signal Pathway Signal Transduction Site Site-Directed Mutagenesis Stress Testing Threonine Von Hippel-Lindau Tumor Suppressor Protein Warburg Effect Withdrawal Woman Xenograft procedure aerobic glycolysis arm base cancer cell cancer type cellular development endoplasmic reticulum stress glucose uptake human FRAP1 protein hypoxia inducible factor 1 in vivo killings malignant breast neoplasm mortality mutant novel novel therapeutics overexpression protein function public health relevance response restoration sensor stress protein transcription factor tumor tumor growth tumor metabolism

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. There is currently no cure for breast cancer and thus a greater understanding of the underlying biology of breast cancer will identify molecular targets and allow for the development of novel therapeutics. Cancer cells exhibit altered metabolism, characterized by increased glucose uptake and increased glycolysis under aerobic condition, a process known as Warburg effect. The exact molecular mechanisms underlying cancers dependency on metabolic pathways is unclear. Regulation of proteins by O- GlcNAcylation, post-translational modifications, is a reversible process that depends on glucose availability and is a powerful mechanism to regulate protein function. In this proposal, we will elucidate the mechanisms of how the nutrient sensor O-GlcNAc transferase (OGT), the enzyme responsible for catalyzing addition of O-GlcNAc to proteins, regulates cancer cell metabolism and survival stress signaling. Preliminary data suggests that O- GlcNAcylation regulates cancer metabolism via regulation of HIF-1¿ in a pVHL-dependent manner. Thus, we hypothesize that O-GlcNAcylation regulates cancer cell metabolism and survival stress signaling through VHL- dependent stabilization of HIF-1¿. In Aim #1, we will determine whether O-GlcNAcylation regulation of cancer cell survival requires ER stress and HIF-1¿ pathways. In Aim #2 we will determine how alterations in O- GlcNAc regulate the tumor suppressor VHL protein and determine its contribution to O-GlcNAc-mediated regulation on cancer cell survival metabolism and survival in vitro and in vivo. These studies will further our understanding of how metabolic reprogramming in cancer cells connects at the molecular level to survival stress pathways and identify novel anticancer pathways.

描述（由适用提供）：乳腺癌是全球妇女中最常见的癌症类型，也是癌症相关死亡率的最常见原因。目前尚无治愈乳腺癌的治疗方法，因此对乳腺癌的潜在生物学有更深入的了解将鉴定分子靶标并允许开发新的疗法。癌细胞暴露了改变的新陈代谢，其特征是在有氧疾病下糖酵素摄取增加和糖酵解增加，这一过程称为Warburg效应。尚不清楚癌症对代谢途径的依赖性的确切分子机制尚不清楚。通过O-Glcnacylation（翻译后修饰）调节蛋白质，是一个可逆的过程，取决于葡萄糖可用性，并且是调节蛋白质功能的有力机制。在此提案中，我们将阐明营养传感器O-GLCNAC转移酶（OGT）的机制，即负责催化O-GLCNAC在蛋白质中添加O-GLCNAC的酶，调节癌细胞代谢和存活应力信号传导。初步数据表明，O-Glcnacylation通过以PVHL依赖性方式调节HIF-1来调节癌症代谢。这就是我们假设O-Glcnacylation通过HIF-1的VHL依赖性稳定化来调节癌细胞的代谢和存活应力信号传导。在AIM＃1中，我们将确定癌细胞存活的O-Glcnacylation调节是否需要ER应力和HIF-1途径。在AIM＃2中，我们将确定O-GLCNAC的改变如何调节抑制肿瘤VHL蛋白，并确定其对O-GLCNAC介导的对癌细胞存活代谢的调节的贡献，并在体外和体内生存。这些研究会进一步，我们了解癌细胞中的代谢重编程如何在分子水平上连接以生存应力途径并识别新颖的抗癌途径。