Mechanisms of Chemically Induced Photosensitivity

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We have demonstrated that a low, non-lethal dose of UVA exposure induces dose-dependent cell cycle progression in human HaCaT keratinocytes. We found that UVA induced cyclin D1 accumulation, while siRNA knockdown of cyclin D1 blocked the UVA-induced cell cycle progression, indicating that this process is mediated by cyclin D1. UVA irradiation also induced AKT activation; when cells were incubated with PI3K/AKT inhibitor or infected with dominant negative AKT, cell cycle progression and proliferation were inhibited, suggesting that AKT activation is involved in UVA-induced cell cycle progression. In contrast, ERK was not activated by UVA exposure; incubation with ERK/MAPK inhibitor had no effect on UVA-induced cell cycle progression. Activation of EGFR was observed after UVA exposure. EGFR kinase inhibitor AG1478 attenuated UVA-induced cell cycle progression, indicating the involvement of EGFR activation. Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of ADAM17 had a similar inhibitory effect, demonstrating that ADAM17 has a role in mediating the UVA-induced cell cycle progression. Consistent with the role of ADAM17, antibody blocking amphiregulin attenuated UVA-induced cell cycle progression, implying the involvement of amphiregulin. Identification of these signaling pathways in UVA-induced cell proliferation will facilitate the development of efficient and safe chemopreventive and therapeutic strategies for skin cancer.We have identified the skin lipid cholesta-5,7,9(11)-trien-3 beta-ol (9-DDHC) as the putative agent responsible for UVA-induced skin photosensitivity in Smith-Lemli-Opitz syndrome patients. 9-DDHC generates singlet oxygen and superoxide upon UVA irradiation, is phototoxic to keratinocytes and is found in higher concentrations in plasma from UVA sensitive patients. We have demonstrated that berberine, the main alkaloid present in Goldenseal, is phototoxic to human retinal pigment epithelial cells and lens cells, while hypericin, found in St Johns Wort, is photototoxic to retinal pigment epithelial cells. We have successfully mapped the intracellular spatial localization of singlet oxygen in keratinocytes using the immuno-spin assay technique. Finally, We have found that the flame retardant 3,3,5,5-tetrabromobisphenol A (TBBPA) is subject to photosensitized oxidation involving singlet molecular oxygen. Wide use of flame retardants such as TBBPA can pose an environmental hazard and it is of interest to investigate how they may degrade.