Protein Kinase C ε Is an Endogenous Photosensitizer That Enhances Ultraviolet Radiation-Induced Cutaneous Damage and Development of Squamous Cell Carcinomas1

Abstract

Chronic exposure to UV radiation (UVR), especially in the UVA (315–400 nm) and UVB (280–315 nm) spectrum of sunlight, is the major risk factor for the development of nonmelanoma skin cancer. UVR is a complete carcinogen, which both initiates and promotes carcinogenesis. We found that protein kinase C ε (PKCε), a member of the phospholipid-dependent threonine/serine kinase family, is an endogenous photosensitizer, the overexpression of which in the epidermis increases the susceptibility of mice to UVR-induced cutaneous damage and development of squamous cell carcinoma. The PKCε transgenic mouse (FVB/N) lines 224 and 215 overexpressed 8- and 18-fold PKCε protein, respectively, over endogenous levels in basal epidermal cells. UVR exposure (1 kJ/m² three times weekly) induced irreparable skin damage in high PKCε-overexpressing mouse line 215. However, the PKCε transgenic mouse line 224, when exposed to UVR (2 kJ/m² three times weekly), exhibited minimum cutaneous damage but increased squamous cell carcinoma multiplicity by 3-fold and decreased tumor latency by 12 weeks. UVR exposure of PKCε transgenic mice compared with wild-type littermates (1) elevated the levels of neither cyclobutane pyrimidine dimer nor pyrimidine (6-4) pyrimidone dimer, (2) reduced the appearance of sunburn cells, (3) induced extensive hyperplasia and increased the levels of mouse skin tumor promoter marker ornithine decarboxylase, and (4) elevated the levels of tumor necrosis factor α (TNFα) and other growth stimulatory cytokines, granulocyte colony–stimulating factor, and granulocyte macrophage colony–stimulating factor. The role of TNFα in UVR-induced cutaneous damage was evaluated using PKCε transgenic mice deficient in TNFα. UVR treatment three times weekly for 13 weeks at 2 kJ/m² induced severe cutaneous damage in PKCε transgenic mice (line 215), which was partially prevented in PKCε-transgenic TNFα-knockout mice. Taken together, the results indicate that PKCε signals UVR-induced TNFα release that is linked, at least in part, to the photosensitivity of PKCε transgenic mice.