Role of desmoglein 1 in regulating redox and growth factor signaling in head and neck cancer

桥粒芯糖蛋白 1 在头颈癌中调节氧化还原和生长因子信号传导的作用

• 批准号: 8834156
• 负责人: Sherry Lee
• 金额: $ 3.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834156
• 关键词: Adherens Junction; Adhesions; Adhesives; Adjuvant Therapy; Affect; Antioxidants; Attenuated; Binding; Cadherins; Cell Adhesion Molecules; Cell membrane; Cells; Clinical; Cytoplasmic Tail; Desmosomes; Development; Disease; EGFR Protein Overexpression; Ectopic Expression; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exhibits; Goals; Growth Factor; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Lead; MAP Kinase Gene; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mechanics; Membrane; Modality; Oral cavity; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Phosphorylation; Production; Protein Tyrosine Phosphatase; Proteins; Ras/Raf; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Stratified Epithelium; Survival Rate; Testing; Tissues; Tumor Markers; antioxidant enzyme; cancer cell; desmoglein 1; improved; keratinocyte differentiation; mutant; new therapeutic target; novel; outcome forecast; peroxiredoxin I; public health relevance; response; scaffold; tumor; tumor progression

 DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is a deadly form of cancer that exhibits overactivation of the epidermal growth factor receptor (EGFR) pathway. However, anti-EGFR inhibitors have not significantly improved patients' survival rates. The long-term goal of this project is to define novel targets and therapeutic modalities that will help to circumvent acquired resistance to current EGFR inhibitors. Critical to maintaining the integrity of stratified epithelia such as the skin and oral cavity, desmosomes are essential intercellular adhesion junctions. Beyond their canonical function as adhesive molecules, our lab has shown that desmosomal components are involved in signaling pathways important in health and in disease, such as cancer. Desmoglein 1 (Dsg1), a desmosomal cadherin, promotes differentiation of keratinocytes by binding to its protein partner Erbin in orde to attenuate downstream EGFR effectors. EGFR activation depends on a localized burst of ROS and HNSCC tumors exhibit a high level of oxidative stress. These observations led me to focus on Dsg1's role in regulating redox signaling at the cell membrane, specifically by binding to an antioxidant enzyme, peroxiredoxin 1 (PRDX1). I hypothesize that Dsg1 inhibits ROS production at the cell membrane by binding to PRDX1 and maintaining its enzymatic activity in order to suppress EGFR activation. I will first determine the extent to which Dsg1 attenuates EGFR signaling in HNSCC cells via suppression of ROS induced by EGFR activation (Aim 1). The effect of Dsg1 expression on intracellular ROS level upon EGFR stimulation will be tested. In addition, oxidants will be used to challenge Dsg1's ability to attenuate phosphorylation of EGFR and its downstream effectors in the presence of excess ROS. Antioxidants will also be employed to determine their effects on attenuating the EGFR pathway in the absence of Dsg1. The second aim is to determine how the Dsg1-PRDX1 interactions affect EGFR signaling in HNSCC. I will test whether Dsg1 is required to bind to PRDX1 at the cell membrane in order to reduce membrane ROS and inhibit EGFR phosphorylation. Testing my central hypothesis will reveal the extent to which Dsg1 regulates the EGFR pathway via suppression of ROS, and will determine the function of a novel interaction between Dsg1 and PRDX1 in head and neck cancer cells. Elucidating the cross-talk between an adhesion molecule and redox signaling may improve HNSCC patient prognosis through interference with oxidative pathways as adjuvant therapy.

 描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是一种表现出表皮生长因子受体（EGFR）通路过度活化的致命癌症。然而，抗EGFR抑制剂并没有显著提高患者的生存率。该项目的长期目标是确定新的靶点和治疗方式，这将有助于避免对当前EGFR抑制剂的获得性耐药性。的关键 桥粒是维持复层上皮如皮肤和口腔的完整性的基本细胞间粘附连接。除了作为粘附分子的典型功能外，我们的实验室还表明桥粒组分参与了对健康和疾病（如癌症）重要的信号通路。桥粒芯糖蛋白1（Desmoglein 1，Dsg 1）是一种桥粒钙粘蛋白，通过与Erbin蛋白结合，减弱下游EGFR效应子，促进角质形成细胞分化。EGFR活化依赖于ROS的局部爆发，HNSCC肿瘤表现出高水平的氧化应激。这些观察使我专注于Dsg 1在调节细胞膜氧化还原信号中的作用，特别是通过与抗氧化酶peroxiredoxin 1（PRDX 1）结合。我推测Dsg 1通过与PRDX 1结合并维持其酶活性来抑制细胞膜上ROS的产生，从而抑制EGFR的活化。我将首先确定Dsg 1通过抑制EGFR激活诱导的ROS而减弱HNSCC细胞中EGFR信号传导的程度（Aim 1）。将测试Dsg 1表达对EGFR刺激后细胞内ROS水平的影响。此外，氧化剂将用于挑战Dsg 1在过量ROS存在下减弱EGFR及其下游效应物磷酸化的能力。还将采用抗氧化剂来确定它们在不存在Dsgl的情况下对减弱EGFR途径的作用。第二个目的是确定Dsg 1-PRDX 1相互作用如何影响HNSCC中的EGFR信号传导。我将测试Dsg 1是否需要在细胞膜上与PRDX 1结合，以减少膜ROS并抑制EGFR磷酸化。测试我的中心假设将揭示Dsg 1通过抑制ROS调节EGFR通路的程度，并将确定Dsg 1和PRDX 1在头颈癌细胞中的新型相互作用的功能。阐明粘附分子和氧化还原信号传导之间的串扰可以通过干扰氧化途径作为辅助治疗来改善HNSCC患者的预后。