Chronic exposure to solar ultraviolet (UV) radiation, particularly UVB (290- 320 nm), is primarily responsible for more than 1,000,000 new cases of nonmelanoma skin cancer each year in the USA alone, making it the most hazardous environmental carcinogen known for humans. Thus, there is an urgent need to develop strategies to prevent the occurrence of these cutaneous malignancies. We and others have previously shown that a polyphenolic fraction isolated from green tea, and particularly its major and the most effective chemopreventive antioxidant constituent (-)-epigallocatechin-3- gallate (EGCG), has remarkable preventive effects against UV-induced skin tumorigenesis in mouse model. The current proposal is designed to define the mechanism through which oral administration of EGCG to SKH-l hairless mice prevents photocarcinogenesis. The central hypothesis to be tested in this proposal is that UVB exposure to skin induces oxidative stress, which causes phosphorylation of epidermal growth factor receptor (EGFR) and mitogen- activated protein kinase (MAPK) signaling pathways leading to the induction of photocarcinogenic events. The corollary to our hypothesis is that orally administered dietary antioxidant EGCG from green tea in drinking water to SKH- l hairless mice will prevent UVB radiation-induced oxidative stress, and thus oxidative stress-mediated phosphorylation of EGFR anc PK signaling pathways. The inhibition of UVB-induced oxidative stress-mediated phosphorylation of cellular signaling by EGCG will result in reduction of skin cancer incidence. Following specific aims are proposed to study in this project: (i) to determine the effect of single or multiple UVB exposures on cutaneous oxidative stress, and preventive effects by dietary antioxidant EGCG against UVB-induced oxidative stress, and (ii) to determine the effect of UVB-induced oxidative stress-caused phosphorylation of EGFR, and MAPK such as extracellular signal-regulated kinase (ERK1/2), JNK and p38 signaling pathways in vivo mouse skin. Preventive effects of EGCG will be determined on UVB- induced oxidative stress mediated phosphorylation of these cell-signaling events. Validation of this hypothesis would help in developing novel dietary intervention approaches and future strategies to prevent solar UV radiation- induced skin cancer development, which may result to protect and prolong the human health and lives.
