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

 描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是一种致命的癌症形式，表现出表皮生长因子受体(EGFR)途径的过度激活。然而，抗EGFR抑制剂并没有显著提高患者的存活率。该项目的长期目标是确定新的靶点和治疗方式，以帮助规避对当前EGFR抑制剂的获得性耐药性。至关重要的是 桥粒是维持皮肤和口腔等复层上皮细胞完整性的重要细胞间黏附连接。除了它们作为黏附分子的典型功能外，我们的实验室还表明，桥粒成分参与了对健康和癌症等疾病至关重要的信号通路。桥粒钙粘附素桥粒蛋白1(DSG1)通过与其蛋白伴侣Erbin结合，促进角质形成细胞分化，从而减弱其下游的EGFR效应。EGFR的激活依赖于局部ROS的爆发，而HNSCC肿瘤表现出高水平的氧化应激。这些观察使我专注于DSG1的S在调节细胞膜上的氧化还原信号中的作用，特别是通过与抗氧化酶Peroxiredox1(PRDX1)结合。我假设DSG1通过与PRDX1结合并保持其酶活性来抑制细胞膜上ROS的产生，从而抑制EGFR的激活。我将首先确定DSG1通过抑制EGFR激活诱导的ROS在多大程度上减弱HNSCC细胞中的EGFR信号(目标1)。DSG1的表达对EGFR刺激的细胞内ROS水平的影响将被测试。此外，氧化剂将被用来挑战DSG1的S在过量ROS存在的情况下减弱EGFR及其下游效应物的磷酸化的能力。在缺乏DSG1的情况下，抗氧化剂也将被用来确定它们在减弱EGFR途径方面的作用。第二个目的是确定DSG1-PRDX1相互作用如何影响HNSCC中的EGFR信号转导。我将测试DSG1是否需要与细胞膜上的PRDX1结合，以减少细胞膜ROS和抑制EGFR磷酸化。验证我的中心假设将揭示DSG1通过抑制ROS来调节EGFR途径的程度，并将确定DSG1和PRDX1之间的一种新的相互作用在头颈部癌细胞中的功能。阐明黏附分子和氧化还原信号之间的串扰可能通过干扰氧化通路作为辅助治疗来改善HNSCC患者的预后。

 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.