Abstract
We recently reported that (23R, 24E)-23-acetoxymangiferonic acid (23R-AMA), a cycloartane triterpenoid isolated by activity-guided separation from a methanol extract of Garcinia sp. bark, inhibited melanin production via inhibition of tyrosinase (TYR) expression in the B16-F10 melanoma cell line. Since 23R-AMA also inhibited microphthalmia-associated transcription factor (MITF) expression, an upstream factor of TYR, these features of 23R-AMA were thought to be appropriate for development of whitening cosmetics. However, 23R-AMA exhibited growth inhibition other than inhibition of melanin production in B16-F10 cells. Therefore, we investigated biological activities of 23R-AMA in detail, focused on its application as an anti-melanoma compound. In this study, we demonstrated that 23R-AMA inhibited cell proliferation and basic FGF (bFGF)-induced migration in B16-F10 cells. Furthermore, 23R-AMA promoted ser45/thr41 phosphorylation of β-catenin and suppressed its intranuclear accumulation, which was suggested to be related to inhibition of MITF expression. The transcriptional activity of MITF is known to be regulated by phosphorylation via activated ERK. Further investigation revealed that 23R-AMA inhibited phosphorylation of c-Raf, MEK-1, and ERK, and also that of upstream molecules including FAK and c-Src. These results suggested that 23R-AMA inhibited growth and migration of B16-F10 melanoma by regulating both MITF expression and its activity. The activities of 23R-AMA reported in this study are new aspects of cycloartane triterpenoids.
Highlights
Melanocytes are cells producing melanin pigments in the basal layer under the epidermis
We recently reported that (23R, 24E)-23-acetoxymangiferonic acid [(23R, 24E)-23-acetoxy-3-oxocycloart-24-en26-oic acid] (23R-AMA), a cycloartane triterpenoid isolated from a methanol extract of Garcinia sp. bark, has inhibitory activity against melanin production via inhibition of TYR expression in the B16-F10 melanoma cell line [6]
We investigated the detailed mode of action of 23R-AMA-induced inhibitory effects on cell proliferation and migration in B16-F10 melanoma, and found that these activities were caused by inhibitory regulation to both microphthalmia-associated transcription factor (MITF) expression and its transcriptional activity, and which were elicited by inhibition of β-catenin and c-Raf–MEK1–ERK signaling axis including focal adhesion kinase (FAK) and c-Src
Summary
Melanocytes are cells producing melanin pigments in the basal layer under the epidermis. Melanoma is a type of skin cancer whose worldwide incidence has steadily increased over the last several decades. Melanoma is known as the most malignant skin cancer with a high fatality rate since its progressing state shows resistance to various treatments. It has been reported that MITF expression is elevated or mutated in melanoma [3]. MITF-M, one of the isoforms of MITF, was reported to be expressed in melanoma cells [4]. Apoptosis of malignant melanoma was induced by functional inhibition of MITF [5]. These reports indicated that MITF is a pathogenic factor in melanoma and a potential target molecule for therapy
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