Dietary flavonoid myricetin 3-O-galactoside suppresses α-melanocyte stimulating hormone-induced melanogenesis in B16F10 melanoma cells by regulating PKA and ERK1/2 activation

Jung Hwan Oh; Fatih Karadeniz; Youngwan Seo; Chang-Suk Kong

doi:10.1515/znc-2023-0039

Article

Dietary flavonoid myricetin 3-O-galactoside suppresses α-melanocyte stimulating hormone-induced melanogenesis in B16F10 melanoma cells by regulating PKA and ERK1/2 activation

Jung Hwan Oh , Fatih Karadeniz , Youngwan Seo and Chang-Suk Kong

Published/Copyright: September 14, 2023

Published by

Become an author with De Gruyter Brill

Submit Manuscript Author Information Explore this Subject

From the journal Zeitschrift für Naturforschung C Volume 78 Issue 11-12

Abstract

Melanogenesis is the process where skin pigment melanin is produced through tyrosinase activity. Overproduction of melanin causes skin disorders such as freckles, spots, and hyperpigmentation. Myricetin 3-O-galactoside (M3G) is a dietary flavonoid with reported bioactivities. M3G was isolated from Limonium tetragonum and its anti-melanogenic properties were investigated in α-melanocyte stimulating hormone-stimulated B16F10 melanoma cells. The in vitro anti-melanogenic capacity of M3G was confirmed by inhibited tyrosinase and melanin production. M3G-mediated suppression of melanogenic proteins, tyrosinase, microphthalmia-associated transcription factor (MITF), and tyrosinase-related proteins (TRP)-1 and TRP-2, were confirmed by mRNA and protein levels, analyzed by RT-qPCR and Western blot, respectively. Furthermore, M3G suppressed Wnt signaling through the inhibition of PKA phosphorylation. M3G also suppressed the consequent phosphorylation of CREB and nuclear levels of MITF. Analysis of MAPK activation further revealed that M3G increased the activation of ERK1/2 while p38 and JNK activation remained unaffected. Results showed that M3G suppressed melanogenesis in B16F10 cells by decreasing tyrosinase production and therefore inhibiting melanin formation. A possible action mechanism was the suppression of CREB activation and upregulation of ERK phosphorylation which might cause the decreased nuclear levels of MITF. In conclusion, M3G was suggested to be a potential nutraceutical with anti-melanogenic properties.

Keywords: CREB; Limonium tetragonum ; melanogenesis; MITF; myricetin 3-O-galactoside; tyrosinase

Corresponding author: Chang-Suk Kong, Marine Biotechnology Center for Pharmaceuticals and Foods, College of Medical and Life Sciences, Silla University, Busan 46958, Republic of Korea; and Department of Food and Nutrition, College of Medical and Life Sciences, Silla University, Busan 46958, Republic of Korea, E-mail: cskong@silla.ac.kr

Funding source: National Research Foundation of Korea

Award Identifier / Grant number: RS-2023-00212560

Award Identifier / Grant number: 2023R1A2C1006268

Acknowledgments

NMR spectral data were kindly provided by Dr. Eun-Hee Kim (Korea Basic Science Institute, Daejeon, Korea).

Research ethics: Not applicable.
Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission. Detailed author contributions are as follows: Conceptualization and methodology, J.H.O., F.K. and C.-S.K.; investigation, writing, and visualization, J.H.O. and F.K.; resources, Y.S. and C.-S.K.; supervision Y.S. and C.-S.K.
Competing interests: The authors declare that they have no competing interests.
Research funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIT) (No. RS-2023-00212560).
Data availability: The raw data is available from the corresponding author upon reasonable request.

References

1. Brenner, M, Hearing, VJ. The protective role of melanin against UV damage in human skin. Photochem Photobiol 2008;84:539–49. https://doi.org/10.1111/j.1751-1097.2007.00226.x.Search in Google Scholar PubMed PubMed Central

2. ElObeid, AS, Kamal-Eldin, A, Abdelhalim, MAK, Haseeb, AM. Pharmacological properties of melanin and its function in health. Basic Clin Pharmacol Toxicol 2017;120:515–22. https://doi.org/10.1111/bcpt.12748.Search in Google Scholar PubMed

3. Lambert, MW, Maddukuri, S, Karanfilian, KM, Elias, ML, Lambert, WC. The physiology of melanin deposition in health and disease. Clin Dermatol 2019;37:402–17. https://doi.org/10.1016/j.clindermatol.2019.07.013.Search in Google Scholar PubMed

4. Nasti, TH, Timares, L. MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer. Photochem Photobiol 2015;91:188–200. https://doi.org/10.1111/php.12335.Search in Google Scholar PubMed PubMed Central

5. Dumbuya, H, Hafez, SY, Oancea, E. Cross talk between calcium and ROS regulate the UVA-induced melanin response in human melanocytes. Faseb J 2020;34:11605–23. https://doi.org/10.1096/fj.201903024r.Search in Google Scholar

6. Chen, J, Liu, Y, Zhao, Z, Qiu, J. Oxidative stress in the skin: impact and related protection. Int J Cosmet Sci 2021;43:495–509. https://doi.org/10.1111/ics.12728.Search in Google Scholar PubMed

7. Zhang, H, Kong, Q, Wang, J, Jiang, Y, Hua, H. Complex roles of cAMP–PKA–CREB signaling in cancer. Exp Hematol Oncol 2020;9:1–13. https://doi.org/10.1186/s40164-020-00191-1.Search in Google Scholar PubMed PubMed Central

8. Goding, CR, Arnheiter, H. MITF – the first 25 years. Genes Dev 2019;33:983–1007. https://doi.org/10.1101/gad.324657.119.Search in Google Scholar PubMed PubMed Central

9. Pillaiyar, T, Namasivayam, V, Manickam, M, Jung, SH. Inhibitors of melanogenesis: an updated review. J Med Chem 2018;61:7395–418. https://doi.org/10.1021/acs.jmedchem.7b00967.Search in Google Scholar PubMed

10. Moon, KM, Yang, JH, Lee, MK, Kwon, EB, Baek, J, Hwang, T, et al.. Maclurin exhibits antioxidant and anti-tyrosinase activities, suppressing melanogenesis. Antioxidants 2022;11:1164. https://doi.org/10.3390/antiox11061164.Search in Google Scholar PubMed PubMed Central

11. Joompang, A, Anwised, P, Luangpraditkun, K, Jangpromma, N, Viyoch, J, Viennet, C, et al.. Anti-melanogenesis activity of crocodile (Crocodylus siamensis) white blood cell extract on ultraviolet B-irradiated melanocytes. J Med Food 2022;25:818–27. https://doi.org/10.1089/jmf.2021.k.0130.Search in Google Scholar PubMed

12. Bodurlar, Y, Caliskan, M. Inhibitory activity of soybean (Glycine max L. Merr.) cell culture extract on tyrosinase activity and melanin formation in alpha-melanocyte stimulating hormone-induced B16-F10 melanoma cells. Mol Biol Rep 2022;49:7827–36. https://doi.org/10.1007/s11033-022-07608-6.Search in Google Scholar PubMed

13. Chen, L, Cao, H, Huang, Q, Xiao, J, Teng, H. Absorption, metabolism and bioavailability of flavonoids: a review. Crit Rev Food Sci Nutr 2022;62:7730–42. https://doi.org/10.1080/10408398.2021.1917508.Search in Google Scholar PubMed

14. Slika, H, Mansour, H, Wehbe, N, Nasser, SA, Iratni, R, Nasrallah, G, et al.. Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed Pharmacother 2022;146:112442. https://doi.org/10.1016/j.biopha.2021.112442.Search in Google Scholar PubMed

15. Alzaabi, MM, Hamdy, R, Ashmawy, NS, Hamoda, AM, Alkhayat, F, Khademi, NN, et al.. Flavonoids are promising safe therapy against COVID-19. Phytochemistry Rev 2022;21:291–312. https://doi.org/10.1007/s11101-021-09759-z.Search in Google Scholar PubMed PubMed Central

16. Dias, MC, Pinto, DCGA, Silva, AMS. Plant flavonoids: chemical characteristics and biological activity. Molecules 2021;26:5377. https://doi.org/10.3390/molecules26175377.Search in Google Scholar PubMed PubMed Central

17. Ahmed, OM, AbouZid, SF, Ahmed, NA, Zaky, MY, Liu, H. An up-to-date review on citrus flavonoids: chemistry and benefits in health and diseases. Curr Pharmaceut Des 2020;27:513–30. https://doi.org/10.2174/18734286mtexcoted5.Search in Google Scholar

18. El-Nashar, HAS, Gamal El-Din, MI, Hritcu, L, Eldahshan, OA. Insights on the inhibitory power of flavonoids on tyrosinase activity: a survey from 2016 to 2021. Molecules 2021;26:7546. https://doi.org/10.3390/molecules26247546.Search in Google Scholar PubMed PubMed Central

19. Huang, CY, Liu, IH, Huang, XZ, Chen, HJ, Chang, ST, Chang, ML, et al.. Antimelanogenesis effects of leaf extract and phytochemicals from Ceylon olive (Elaeocarpus serratus) in zebrafish model. Pharmaceutics 2021;13:1059. https://doi.org/10.3390/pharmaceutics13071059.Search in Google Scholar PubMed PubMed Central

20. Karadeniz, F, Oh, JH, Jo, HJ, Seo, Y, Kong, CS. Myricetin 3-o-β-d-galactopyranoside exhibits potential anti-osteoporotic properties in human bone marrow-derived mesenchymal stromal cells via stimulation of osteoblastogenesis and suppression of adipogenesis. Cells 2021;10:2690. https://doi.org/10.3390/cells10102690.Search in Google Scholar PubMed PubMed Central

21. Oh, JH, Karadeniz, F, Lee, JI, Park, SY, Seo, Y, Kong, CS. Anticatabolic and anti-inflammatory effects of myricetin 3-O-β-d-galactopyranoside in UVA-irradiated dermal cells via repression of MAPK/AP-1 and activation of TGFβ/Smad. Molecules 2020;25:1331. https://doi.org/10.3390/molecules25061331.Search in Google Scholar PubMed PubMed Central

22. Azevedo, Ade O, Campos, JJ, de Souza, GG, Veloso Cde, C, Duarte, ID, Braga, FC, et al.. Antinociceptive and anti-inflammatory effects of myricetin 3-O-β-galactoside isolated from Davilla elliptica: involvement of the nitrergic system. J Nat Med 2015;69:487–93. https://doi.org/10.1007/s11418-015-0913-9.Search in Google Scholar PubMed

23. Lee, SG, Karadeniz, F, Seo, Y, Kong, CS. Anti-melanogenic effects of flavonoid glycosides from Limonium tetragonum (Thunb. bullock) via inhibition of tyrosinase and tyrosinase-related proteins. Molecules 2017;22:1480. https://doi.org/10.3390/molecules22091480.Search in Google Scholar PubMed PubMed Central

24. Lee, JI, Kong, CS, Jung, ME, Hong, JW, Lim, SY, Seo, Y. Antioxidant activity of the halophyte Limonium tetragonum and its major active components. Biotechnol Bioproc Eng 2011;16:992–9. https://doi.org/10.1007/s12257-011-0213-5.Search in Google Scholar

25. Lee, CS, Park, M, Han, J, Lee, JH, Bae, IH, Choi, H, et al.. Liver X receptor activation inhibits melanogenesis through the acceleration of ERK-mediated MITF degradation. J Invest Dermatol 2013;133:1063–71. https://doi.org/10.1038/jid.2012.409.Search in Google Scholar PubMed

26. Takekoshi, S, Nagata, H, Kitatani, K. Flavonoids enhance melanogenesis in human melanoma cells. Tokai J Exp Clin Med 2014;39:116–21.Search in Google Scholar

27. Rodríguez, CI, Setaluri, V. Cyclic AMP (cAMP) signaling in melanocytes and melanoma. Arch Biochem Biophys 2014;563:22–7. https://doi.org/10.1016/j.abb.2014.07.003.Search in Google Scholar PubMed

28. Hwang, YS, Oh, SW, Park, SH, Lee, J, Yoo, JA, Kwon, K, et al.. Melanogenic effects of maclurin are mediated through the activation of cAMP/PKA/CREB and p38 MAPK/CREB signaling pathways. Oxid Med Cell Longev 2019;2019:9827519. https://doi.org/10.1155/2019/9827519.Search in Google Scholar PubMed PubMed Central

29. Larue, L. The Wnt/beta-catenin pathway in melanoma. Front Biosci 2006;11:733. https://doi.org/10.2741/1831.Search in Google Scholar PubMed

30. D’Mello, SAN, Finlay, GJ, Baguley, BC, Askarian-Amiri, ME. Signaling pathways in melanogenesis. Int J Mol Sci 2016;17:1144. https://doi.org/10.3390/ijms17071144.Search in Google Scholar PubMed PubMed Central

31. Yoon, HS, Lee, SR, Ko, HC, Choi, SY, Park, JG, Kim, JK. Involvement of extracellular signal-regulated kinase in nobiletin-induced melanogenesis in murine B16/F10 melanoma cells. Biosci Biotechnol Biochem 2007;71:1781–4. https://doi.org/10.1271/bbb.70088.Search in Google Scholar PubMed

32. Kim, ES, Park, SJ, Goh, MJ, Na, YJ, Jo, DS, Jo, YK, et al.. Mitochondrial dynamics regulate melanogenesis through proteasomal degradation of MITF via ROS-ERK activation. Pigm Cell Melanoma Research 2014;27:1051–62. https://doi.org/10.1111/pcmr.12298.Search in Google Scholar PubMed

33. Bang, J, Zippin, JH. Cyclic adenosine monophosphate (cAMP) signaling in melanocyte pigmentation and melanomagenesis. Pigm Cell Melanoma Research 2020;34:28–43. https://doi.org/10.1111/pcmr.12920.Search in Google Scholar PubMed

34. Englaro, W, Rezzonico, R, Durand-Clément, M, Lallemand, D, Ortonne, JP, Ballotti, R. Mitogen-activated protein kinase pathway and AP-1 are activated during cAMP-induced melanogenesis in B-16 melanoma cells. J Biol Chem 1995;270:24315–20. https://doi.org/10.1074/jbc.270.41.24315.Search in Google Scholar PubMed

35. Hayder, N, Bouhlel, I, Skandrani, I, Kadri, M, Steiman, R, Guiraud, P, et al.. In vitro antioxidant and antigenotoxic potentials of myricetin-3-o-galactoside and myricetin-3-o-rhamnoside from Myrtus communis: modulation of expression of genes involved in cell defence system using cDNA microarray. Toxicol Vitro 2008;22:567–81. https://doi.org/10.1016/j.tiv.2007.11.015.Search in Google Scholar PubMed

Received: 2023-03-29

Accepted: 2023-08-26

Published Online: 2023-09-14

Published in Print: 2023-11-27

You are currently not able to access this content.

Articles in the same Issue

https://doi.org/10.1515/znc-2023-0039

Keywords for this article

CREB; Limonium tetragonum; melanogenesis; MITF; myricetin 3-O-galactoside; tyrosinase