Marliolide Derivative Induces Melanosome Degradation via Nrf2/p62-Mediated Autophagy

Int J Mol Sci. 2021 Apr 13;22(8):3995. doi: 10.3390/ijms22083995.

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2), which is linked to autophagy regulation and melanogenesis regulation, is activated by marliolide. In this study, we investigated the effect of a marliolide derivative on melanosome degradation through the autophagy pathway. The effect of the marliolide derivative on melanosome degradation was investigated in α-melanocyte stimulating hormone (α-MSH)-treated melanocytes, melanosome-incorporated keratinocyte, and ultraviolet (UV)B-exposed HRM-2 mice (melanin-possessing hairless mice). The marliolide derivative, 5-methyl-3-tetradecylidene-dihydro-furan-2-one (DMF02), decreased melanin pigmentation by melanosome degradation in α-MSH-treated melanocytes and melanosome-incorporated keratinocytes, evidenced by premelanosome protein (PMEL) expression, but did not affect melanogenesis-associated proteins. The UVB-induced hyperpigmentation in HRM-2 mice was also reduced by a topical application of DMF02. DMF02 activated Nrf2 and induced autophagy in vivo, evidenced by decreased PMEL in microtubule-associated proteins 1A/1B light chain 3B (LC3)-II-expressed areas. DMF02 also induced melanosome degradation via autophagy in vitro, and DMF02-induced melanosome degradation was recovered by chloroquine (CQ), which is a lysosomal inhibitor. In addition, Nrf2 silencing by siRNA attenuated the DMF02-induced melanosome degradation via the suppression of p62. DMF02 induced melanosome degradation in melanocytes and keratinocytes by regulating autophagy via Nrf2-p62 activation. Therefore, Nrf2 activator could be a promising therapeutic agent for reducing hyperpigmentation.

Keywords: Nrf2; autophagy; melanosome degradation; p62.

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Autophagy* / radiation effects
  • Gene Knockdown Techniques
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / radiation effects
  • Lactones / chemistry
  • Lactones / pharmacology*
  • Male
  • Melanins / metabolism
  • Melanocytes / drug effects
  • Melanocytes / metabolism
  • Melanocytes / radiation effects
  • Melanoma, Experimental / pathology
  • Melanosomes / metabolism*
  • Mice
  • NF-E2-Related Factor 2 / metabolism*
  • Sequestosome-1 Protein / metabolism*
  • Skin Pigmentation / drug effects
  • Skin Pigmentation / radiation effects
  • Ultraviolet Rays

Substances

  • Lactones
  • Melanins
  • NF-E2-Related Factor 2
  • Sequestosome-1 Protein
  • marliolide