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
- 125 Downloads
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.
KeywordsGarcinia Triterpenoids Cycloartane Melanoma MITF β-Catenin ERK c-Raf
This work was supported by Grants in-Aid for Scientific Research from The Japan Society for the Promotion of Science, Japan.
- 2.Matthews NH, Li W-Q, Qureshi AA, Weinstock MA, Cho E (2017) Epidemiology of melanoma. In: Ward WH, Farma JM (eds) Cutaneous melanoma: etiology and therapy. Codon, BrisbaneGoogle Scholar
- 3.Garraway LA, Widlund HR, Rubin MA, Getz G, Berger AJ, Ramaswamy S, Beroukhim R, Milner DA, Granter SR, Du J, Lee C, Wagner SN, Li C, Golub TR, Rimm DL, Meyerson ML, Fisher DE, Sellers WR (2005) Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436:117CrossRefPubMedGoogle Scholar
- 5.Larribere L, Hilmi C, Khaled M, Gaggioli C, Bille K, Auberger P, Ortonne JP, Ballotti R, Bertolotto C (2005) The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis. Genes Dev 19:1980–1985CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Nugroho AE, Matsumoto M, Sotozono Y, Kaneda T, Hadi AHA, Morita H (2018) Cycloartane triterpenoids with anti-melanin deposition activity. Nat Prod Commun 13(7):809–812Google Scholar
- 11.Toume K, Nakazawa T, Hoque T, Ohtsuki T, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M (2012) Cycloartane triterpenes and ingol diterpenes isolated from Euphorbia neriifolia in a screening program for death-receptor expression-enhancing activity. Planta Med 78:1370–1377CrossRefPubMedGoogle Scholar
- 20.Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949CrossRefPubMedGoogle Scholar
- 23.Bosnjak M, Dolinsek T, Cemazar M, Kranjc S, Blagus T, Markelc B, Stimac M, Zavrsnik J, Kamensek U, Heller L, Bouquet C, Turk B, Sersa G (2015) Gene electrotransfer of plasmid AMEP, an integrin-targeted therapy, has antitumor and antiangiogenic action in murine B16 melanoma. Gene Ther 22:578CrossRefPubMedGoogle Scholar
- 28.McGill GG, Horstmann M, Widlund HR, Du J, Motyckova G, Nishimura EK, Lin Y-L, Ramaswamy S, Avery W, Ding H-F, Jordan SA, Jackson IJ, Korsmeyer SJ, Golub TR, Fisher DE (2002) Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109:707–718CrossRefPubMedGoogle Scholar
- 32.Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Haber DA, Settleman J (2008) Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res 68:4853–4861CrossRefPubMedPubMedCentralGoogle Scholar