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Cycloartane triterpenoid (23R, 24E)-23-acetoxymangiferonic acid inhibited proliferation and migration in B16-F10 melanoma via MITF downregulation caused by inhibition of both β-catenin and c-Raf–MEK1–ERK signaling axis

  • Toshio Kaneda
  • Misaki Matsumoto
  • Yayoi Sotozono
  • Satoshi Fukami
  • Alfarius Eko Nugroho
  • Yusuke Hirasawa
  • Hadi A. Hamid A
  • Hiroshi Morita
Original Paper
  • 125 Downloads

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.

Keywords

Garcinia Triterpenoids Cycloartane Melanoma MITF β-Catenin ERK c-Raf 

Notes

Acknowledgement

This work was supported by Grants in-Aid for Scientific Research from The Japan Society for the Promotion of Science, Japan.

Supplementary material

11418_2018_1233_MOESM1_ESM.pdf (337 kb)
Supplementary material 1 (PDF 336 kb)

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Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Toshio Kaneda
    • 1
  • Misaki Matsumoto
    • 1
  • Yayoi Sotozono
    • 1
  • Satoshi Fukami
    • 1
  • Alfarius Eko Nugroho
    • 1
  • Yusuke Hirasawa
    • 1
  • Hadi A. Hamid A
    • 2
  • Hiroshi Morita
    • 1
  1. 1.Faculty of Pharmaceutical SciencesHoshi UniversityTokyoJapan
  2. 2.Department of Chemistry, Faculty of ScienceUniversity MalayaKuala LumpurMalaysia

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