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.
Project 2 (Dong, Bode) TOPK/PRPK as Novel Targets for Skin Cancer Prevention Skin cancer is the most common human cancer and the number one cancer in terms of incidence in the USA and sunlight is a major risk factor. The use of sunscreens or sun blocks has not been sufficiently effective in preventing skin cancer, and therefore new mechanism-based approaches are critically needed to treat and prevent skin cancer caused by sunlight. We have identified two proteins expressed in skin that play critical roles in sun-induced skin cancer. Preliminary data suggest that decreasing the activity of either one can completely or almost completely prevent sunlight-induced skin cancer, indicating that these proteins are novel diagnostic markers and significant targets for the development of therapeutic agents to prevent and treat non- melanoma skin cancers.
