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 β‐mangostin from seedcases of Garcinia mangostana inhibited α‐melanocyte‐stimulating hormone (α‐MSH)‐mediated melanogenesis in B16F10 melanoma cells and a three‐dimensional human skin model. β‐Mangostin significantly inhibited the protein level of tyrosinase induced by α‐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 β‐mangostin treatment. However, rapamycin, a representative non‐selective autophagy inducer, triggered autophagy in α‐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 β‐mangostin‐treated cells. Taken together, our results suggest that β‐mangostin inhibits the melanogenesis induced by α‐MSH via an autophagy‐dependent mechanism, and thus, the depigmentation effect of β‐mangostin may depend on autophagy targeted at the melanosome rather than non‐selective autophagy.