Depigmentation of α-melanocyte-stimulating hormone-treated melanoma cells by β-mangostin is mediated by selective autophagy

Melanogenesis is a key pathway for the regulation of skin pigmentation and the development of skin-lightening/skin-whitening drugs or cosmetics. In this study, we found that beta-mangostin from seedcases of Garcinia mangostana inhibited alpha-melanocyte-stimulating hormone (alpha-MSH)-mediated melanogenesis in B16F10 melanoma cells and a three-dimensional human skin model. beta-Mangostin significantly inhibited the protein level of tyrosinase induced by alpha-MSH in UPS (ubiquitin proteasome system)-independent and lysosome-dependent manner. The inhibition of autophagy by 3-methyladenine treatment or ATG5 knockdown effectively recovered premelanosome protein as well as tyrosinase degraded by the beta-mangostin treatment. However, rapamycin, a representative non-selective autophagy inducer, triggered autophagy in alpha-MSH-stimulated cells, which was characterized by a considerable decrease in p62, but it was unable to inhibit melanogenesis. Melanosome-engulfing autophagosomes were observed using transmission electron microscopy. Furthermore, previously formed melanin could be degraded effectively in an autophagy-dependent manner in beta-mangostin-treated cells. Taken together, our results suggest that beta-mangostin inhibits the melanogenesis induced by alpha-MSH via an autophagy-dependent mechanism, and thus, the depigmentation effect of beta-mangostin may depend on autophagy targeted at the melanosome rather than non-selective autophagy.