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

• Published in: International journal of molecular sciences Vol. 22; no. 8; p. 3995
• Main Authors: Yun, Cheong-Yong, Choi, Nahyun, Lee, Jae Un, Lee, Eun Jung, Kim, Ji Young, Choi, Won Jun, Oh, Sang Ho, Sung, Jong-Hyuk
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.04.2021; MDPI
• Subjects: Animals; Antioxidants; Autophagy; Autophagy - drug effects; Autophagy - radiation effects; Chemical compounds; Chloroquine; Degradation; Enzymes; Gene Knockdown Techniques; Hairless; Humans; Hyperpigmentation; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - radiation effects; Lactones - chemistry; Lactones - pharmacology; Male; Melanin; Melanins - metabolism; Melanocytes; Melanocytes - drug effects; Melanocytes - metabolism; Melanocytes - radiation effects; Melanoma; Melanoma, Experimental - pathology; melanosome degradation; Melanosomes - metabolism; Mice; Microscopy; Microtubule-associated proteins; NF-E2-Related Factor 2 - metabolism; Nrf2; Oxidative stress; p62; Phagocytosis; Pharmacology; Pigmentation; Proteins; Senescence; Sequestosome-1 Protein - metabolism; siRNA; Skin; Skin Pigmentation - drug effects; Skin Pigmentation - radiation effects; Topical application; Transcription factors; Ultraviolet radiation; Ultraviolet Rays; melanosome degradation; autophagy; Nrf2; p62
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22083995

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.