Cell fate regulated by nuclear factor-κB- and activator protein-1-dependent signalling in human melanocytes exposed to ultraviolet A and ultraviolet B

SUMMARY: BACKGROUND: Ultraviolet (UV) radiation constitutes an important risk factor for malignant melanoma, but the wavelength responsible for the initiation of this disease is not fully elucidated. Solar UV induces multiple signalling pathways that are critical for initiation of apoptotic cell death as a cellular defence against malignant transformation. OBJECTIVES: To evaluate the involvement of the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1 in the signalling pathways induced by UVA or UVB irradiation in human melanocytes. METHODS: Primary cultures of normal human melanocytes were irradiated with UVA or UVB, and the concomitant DNA damage and redox alterations were monitored. The resulting activation of the NF-κB and AP-1 signalling pathways and subsequent apoptosis were studied. RESULTS: UVB irradiation causes DNA damage detected as formation of cyclobutane pyrimidine dimers, while UVA induces increased levels of 8-hydroxydeoxyguanosine and lipid peroxidation. UVA and UVB initiate phosphorylation of c-Jun N-terminal protein kinase and extracellular signal-regulated kinase, and the apoptosis signalling pathways converge into a common mechanism. Downregulation of c-Jun suppresses AP-1-mediated signalling and prevents apoptosis upstream of lysosomal and mitochondrial membrane permeabilization, whereas inhibition of NF-κB by SN50 increases apoptosis. CONCLUSIONS: We conclude that AP-1 induces proapoptotic signalling, whereas NF-κB is a key antiapoptotic/prosurvival factor in both UVA- and UVB-induced cellular damage in human melanocytes, which might in turn impact melanoma development and progression. WHAT'S ALREADY KNOWN ABOUT THIS TOPIC? Melanocytes are the target cells of ultraviolet (UV) irradiation, and the cells from which melanoma originates. . The mitogen-activated protein kinase signalling pathway is important for regulation of UV-induced cellular responses. . Previous studies have strongly implicated the transcription factors activator protein (AP)-1 and nuclear factor (NF)-κB as mediators of the UV response in other cell types. . WHAT DOES THIS STUDY ADD? The present study identifies NF-κB as an antiapoptotic/prosurvival factor and shows that AP-1 stimulates proapoptotic signalling during both UVA- and UVB-induced apoptosis in human melanocytes. . An improved understanding of cellular responses in UV-exposed melanocytes is essential to understanding and preventing the formation of melanoma, and might provide an opportunity to identify apoptotic regulators. .