Abstract
The anti-melanogenesis effect of glyceollins was examined by melanin synthesis, tyrosinase activity assay in zebrafish embryos and in B16F10 melanoma cells. When developing zebrafish embryos were treated with glyceollins, pigmentation of the embryos, melanin synthesis and tyrosinase activity were all decreased compared with control zebrafish embryos. In situ expression of a pigment cell-specific gene, Sox10, was dramatically decreased by glyceollin treatment in the neural tubes of the trunk region of the embryos. Stem cell factor (SCF)/c-kit signaling pathways as well as expression of microphthalmia-associated transcription factor (MITF) were determined by western blot analysis. Glyceollins inhibited melanin synthesis, as well as the expression and activity of tyrosinase induced by SCF, in a dose-dependent manner in B16F10 melanoma cells. Pretreatment of B16F10 cells with glyceollins dose-dependently inhibited SCF-induced c-kit and Akt phosphorylation. Glyceollins significantly impaired the expression and activity of MITF. An additional inhibitory function of glyceollins was to effectively downregulate intracellular cyclic AMP levels stimulated by SCF in B16F10 cells. Glyceollins have a depigmentation/whitening activity in vitro and in vivo, and that this effect may be due to the inhibition of SCF-induced c-kit and tyrosinase activity through the blockade of downstream signaling pathway.
Highlights
Melanin is a dark pigment that has an essential role in protection against ultraviolet radiation, and its production is restricted to B5% of skin cells that have a common embryological origin and a unique cell type: melanocytes
We studied the role of putative inhibitors of stem cell factor (SCF)/c-kit signaling in cultured melanoma cells, which provide an in vitro model for melanocytes, and in a zebrafish animal model, as detailed below
Glyceollins suppressed SCF-induced AKT and p38-MAPK phosphorylation (Figure 5a). These results suggest that glyceollins successfully suppressed SCF-induced c-kit activation and downstream kinase signaling pathways involved in the function of melanocytes and melanin synthesis
Summary
Melanin is a dark pigment that has an essential role in protection against ultraviolet radiation, and its production is restricted to B5% of skin cells that have a common embryological origin and a unique cell type: melanocytes. Many cytokines that influence survival, proliferation, differentiation and function have been identified in melanocytes.. Many cytokines that influence survival, proliferation, differentiation and function have been identified in melanocytes.2 Besides their gross phenotypic reaction, the response of melanocytes to cytokines is in general poorly understood. SCF/c-kit signaling is known to be involved in melanocyte development during embryogenesis by the analysis of Sl and W knockout mice. Several lines of evidence demonstrate the role of SCF/c-kit signaling in the regulation of epidermal melanogenesis under homeostatic, stimulatory or pathogenic conditions, including ultraviolet B exposure and pigmentation disorders.. Receptor dimerization is followed by autophosphorylation, with the subsequent activation of a downstream signaling cascade. This cascade involves the stimulation of phosphatidylinositol 30-kinase and Ras-mitogen-activated protein kinase (Ras-MAPK) through
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