This dissertation is composed of two parts. In the first part, we focused on the molecular mechanism of ultraviolet B (UVB)-induced cell damage and the roles of nitric oxide (NO) and intracellular zinc in this process. We demonstrated that cell apoptosis, necrosis and skin tissue damage upon UVB-irradiation were mediated through the regulation of oxidative stress-related cellular signaling circuit. The activation of constitutive nitric oxide synthase (NOS) and generation of peroxynitrite (ONOO-) were shown as the causes of skin cell damage. UVB also induced an elevation of intracellular free Zn2+ within two minutes of exposure, which was dependent on the activation of cNOS and the production of peroxynitrite (ONOO-). We showed that the released free Zn2+ was not a cause of UVB-induced apoptosis since removal of free Zn2+ by a low concentration of Zn2+-specific chelator had no effects on UVB-induced apoptosis. However, a high concentration of the Zn2+ chelator was cytotoxic to cells and induced cNOS uncoupling. Our data suggest that oxidative stress causes intracellular free zinc release and induces cNOS uncoupling, which is critical for UVB-induced apoptosis.
In the second part, we characterized the expression level of very late antigen-4 (VLA-4, alpha4beta1) integrin modulated by UVB irradiation and the function of VLA-4 on melanoma metastasis after UVB irradiation. UVB is considered a significant risk factor and an indirect cause of melanoma formation. However, little is known about the potential effects of UVB in melanoma metastasis. The present data show that at 3 hours, 12 hours and 18 hours post-UVB irradiation, VLA-4 expression was unchanged relative to untreated cells, but adhesion to its endothelial ligand vascular cell adhesion molecule-1 (VCAM-1) decreased significantly. Further studies imply that the spatial organization of alpha4 subunit on the melanoma cell surface contributes to the changes in avidity for VCAM-1 upon UVB irradiation. Understanding of the molecular mechanism underlying melanoma-endothelia interactions upon UVB irradiation can guide the development of clinical treatments for melanoma.