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

• 批准号: 10252870
• 负责人: REBECCA Jane MORRIS
• 金额: $ 16.03万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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/10252870
• 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 Proliferation; Cell physiology; Cells; Cessation of life; Chemoprevention; Chronic; Colorectal; Cyclic AMP-Dependent Protein Kinases; 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; MEKs; Malignant Neoplasms; Medical; Mitogen-Activated Protein Kinase Kinases; Modeling; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neoplastic Cell Transformation; Non-Cutaneous Melanoma; Oncogenic; Operative Surgical Procedures; PTGS2 gene; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Play; Prevention; Preventive; 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; Sunlight; Sunscreening Agents; System; TP53 gene; Testing; The Sun; Time; Topical application; Tumor Cell Invasion; Tumor Promoters; UV induced; base; clinical implementation; cyclooxygenase 2; diagnostic biomarker; draining lymph node; effectiveness testing; improved; in vivo; inhibitor/antagonist; keratinocyte; leukemia/lymphoma; melanoma; member; mortality; mouse model; neoplastic cell; novel; novel diagnostics; premalignant; prevent; programs; protein kinase inhibitor; skin cancer prevention; skin lesion; skin squamous cell carcinoma; sunlight-induced; survivin; therapeutic development; tumor; tumor growth; ultraviolet

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.

摘要 项目2(董伯德)TOPK/PRPK作为皮肤癌预防的新靶点 太阳紫外线(SUV)是一种环境致癌物质，会导致炎症和癌症。值得注意的是， 非黑色素瘤皮肤癌(NMSC)的发病率呈逐年上升趋势。减少皮肤病的发生率 鳞状细胞癌(CSCCs)不仅可以降低潜在的严重发病率和死亡率，而且 也大大减少了与手术和医疗相关的数十亿美元的医疗账单 NMSCs需要。因此，确定CSCC发生发展过程中的信号分子是至关重要的。 我们最近发现了两个非常有希望的新蛋白质靶点来预防SUV诱导的皮肤癌，并将 与项目1和项目3合作，将重点放在更新中的那些激酶上。T-LAK细胞起源的蛋白激酶 丝氨酸苏氨酸激酶(TOPK)是丝裂原活化蛋白激酶(MAPKK)家族中的一员， 并参与肿瘤的发展、生长、细胞凋亡和炎症。TOPK在一种 多种癌症，包括NMSCs和黑色素瘤。我们还发现P53相关蛋白激酶(PRPK)、 它位于TOPK的下游，在皮肤癌的发展中起着关键作用。这个项目的目的是检查 TOPK和PRPK在SSL诱导的皮肤癌中的作用及验证新型TOPK和PRPK的有效性 用于预防SUV诱发皮肤癌的抑制剂。在这项提议中要检验的假设是TOPK和 PrPK在SSL诱导的皮肤癌发生中起作用，是新的诊断标志物和重要的 用于预防和治疗NMSCs的治疗剂的开发目标。因为我们的初步数据 研究表明，靶向TOPK或PRPK几乎可以完全阻止太阳紫外线诱导的皮肤癌，我们预计数据 这个项目有可能完全否定皮肤癌无法预防的想法。