Sorafenib induces pigmentation via the regulation of beta-catenin signalling pathway in melanoma cells

Abstract

We conducted large-scale screening test on drugs that were already approved for other diseases to find pigmentation-modulating agents. Among drugs with potential for pigmentation control, we selected sorafenib and further investigated the effect on pigmentation using HM3KO melanoma cells. As a result of treating melanoma cells with sorafenib, pigmentation was promoted in terms of melanin content and tyrosinase activity. Sorafenib increased mRNA and protein levels of pigmentation-related genes such as MITF, tyrosinase and TRP1. To uncover the action mechanism, we investigated the effect of sorafenib on the intracellular signalling pathways. Sorafenib reduced phosphorylation of AKT and ERK, suggesting that sorafenib induces pigmentation through inhibition of the AKT and ERK pathways. In addition, sorafenib significantly increased the level of active beta-catenin, together with activation of beta-catenin signalling. Mechanistic study revealed that sorafenib decreased phosphorylation of serine 9 (S9) of GSK3 beta, while it increased phosphorylation of tyrosine 216 (Y216) of GSK3 beta. These results suggest that sorafenib activates the beta-catenin signalling through the regulation of GSK3 beta phosphorylation, thereby affecting the pigmentation process.