Project 2: TOPK/PRPK as Novel Targets for Skin Cancer Prevention

项目2：TOPK/PRPK作为皮肤癌预防新靶点

基本信息

批准号：
10686370
负责人：
REBECCA Jane MORRIS
金额：
$ 16万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686370
关键词：
Accounting Actinic keratosis Apoptosis Apoptosis Inhibitor Attenuated Basal cell carcinoma Breast Bromides Cancer Cell Growth Cancer Etiology Cell Culture Techniques Cell Line Cell physiology Cells Cessation of life Chemoprevention Chronic Colorectal Dangerousness Data Development Distant Effectiveness Environmental Carcinogens Epidermis FDA approved Family Fusidic Acid General Population Genes Growth Health Human Incidence Inflammation Inflammatory Response KRP protein Knock-out Legal patent Light Lung Lymphokine-Activated Killer Cells Lymphoma MEKs Malignant Neoplasms Medical Mitogen-Activated Protein Kinase Kinases Modeling Morbidity - disease rate Mus Neoplasm Metastasis Neoplastic Cell Transformation Oncogenic Operative Surgical Procedures Pathway interactions Pharmaceutical Preparations Phosphotransferases Play Prevention Preventive Proliferating Prostaglandin Production Prostaglandins Protein Kinase Protein-Serine-Threonine Kinases Proteins Ras/Raf Risk Factors Role Signal Pathway Signal Transduction Signaling Molecule Site Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Stimulation of Cell Proliferation Sunlight Sunscreening Agents System TP53 gene Testing Time Topical application Tumor Cell Invasion Tumor Promoters UV Radiation Exposure UV induced Ultraviolet Rays clinical implementation cyclooxygenase 2 diagnostic biomarker draining lymph node effectiveness testing improved in vivo inhibitor keratinocyte leukemia melanoma member mortality mouse model neoplastic cell novel novel diagnostics p53 related protein kinase pharmacologic premalignant prevent programs protein kinase inhibitor skin cancer prevention skin lesion skin squamous cell carcinoma solar ultraviolet radiation sunlight-induced survivin therapeutic development tumor tumor growth ultraviolet

项目摘要

ABSTRACT Project 2 (Dong, Bode) TOPK/PRPK as Novel Targets for Skin Cancer Prevention Solar ultraviolet (sUV) light is an environmental carcinogen that causes inflammation and cancer. Notably, the incidence of non-melanoma skin cancer (NMSC) is increasing yearly. Reducing the incidence of cutaneous squamous cell carcinomas (cSCCs) would not only reduce their potentially severe morbidity and mortality, but also dramatically reduce the multibillion dollar health bill associated with surgical and medical treatments required for NMSCs. Thus identifying the signaling molecules in the development of cSCC is critically important. We recently discovered 2 new very promising protein targets for preventing sUV-induced skin cancer and will focus on those kinases in this renewal working with Projects 1 and 3. The T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase, is a member of the mitogen-activated protein kinase kinase (MAPKK) family, and is involved in tumor development, growth, apoptosis, and inflammation. TOPK is highly expressed in a variety of cancers, including NMSCs and melanoma. We also found that p53-related protein kinase (PRPK), which is downstream of TOPK, is a crucial player in skin cancer development. This project is aimed to examine the role of TOPK and PRPK in SSL-induced skin cancer and to test the effectiveness of novel TOPK and PRPK inhibitors in preventing sUV-induced skin cancer. The hypothesis to be tested in this proposal is that TOPK and PRPK play functional roles in SSL-induced skin carcinogenesis and are novel diagnostic markers and important targets for the development of therapeutic agents to prevent and treat NMSCs. Because our preliminary data showed that targeting TOPK or PRPK can almost totally block solar UV-induced skin cancer, we expect that data from this project have the potential to completely negate the idea that skin cancer cannot be prevented.

抽象的项目2（Dong，Bode）TOPK/PRPK作为预防皮肤癌的新目标太阳能紫外线（SUV）光是导致炎症和癌症的环境致癌。值得注意的是非黑色素瘤皮肤癌（NMSC）的发生率每年增加。减少皮肤的发生率鳞状细胞癌（CSCC）不仅会降低其潜在的严重发病率和死亡率，而且还会降低还大大减少了与手术和医疗治疗相关的数十亿美元的健康费用 NMSC所需。因此，在CSCC发展中鉴定信号分子至关重要。我们最近发现了2个新的非常有前途的蛋白质靶标，用于预防SUV诱导的皮肤癌，并将专注于与项目1和3一起工作的续订中的那些激酶。T-LAK细胞原始的蛋白激酶（TOPK），一种丝氨酸 - 硫代激酶，是有丝分裂原激活蛋白激酶激酶（MAPKK）家族的成员，并参与肿瘤发育，生长，凋亡和炎症。 Topk在A中高度表达包括NMSC和黑色素瘤在内的各种癌症。我们还发现p53相关蛋白激酶（PRPK）， Topk的下游是皮肤癌发展中的重要参与者。该项目的目的是检查 TOPK和PRPK在SSL诱导的皮肤癌中的作用，并测试新型TOPK和PRPK的有效性防止SUV诱导的皮肤癌的抑制剂。该提议中要检验的假设是Topk和 PRPK在SSL诱导的皮肤致癌作用中扮演功能角色，并且是新颖的诊断标记和重要的开发治疗剂以预防和治疗NMSC的靶标。因为我们的初步数据表明靶向TOPK或PRPK几乎可以完全阻止太阳紫外线引起的皮肤癌，我们希望数据该项目有可能完全消除无法预防皮肤癌的观念。