Dasatinib, a second-generation tyrosine kinase inhibitor, induces melanogenesis via ERK-CREB-MITF-tyrosinase signaling in normal human melanocytes

Abstract

Dasatinib, a second-generation tyrosine kinase inhibitor, is indicated for the therapy of imatinib-resistant leukemia and also for the treatment of solid cancers. Here, we report a novel effect of dasatinib of inducing differentiation in normal human melanocytes. Treatment with dasatinib significantly increased the melanin content and tyrosinase activity through the up-regulation of MITF and tyrosinase expressions. Consistently, dasatinib had clear stimulatory action in the pigmentation of ex vivo cultured skin. The molecular mechanism underlying the melanogenic effect of dasatinib was associated with the ERK-dependent phosphorylation of CREB. The ERK inhibitor PD98059 not only inhibited the phosphorylation of CREB but also abrogated dasatinib-induced melanocyte differentiation. These results demonstrate for the first time the capacity of dasatinib to induce differentiation in normal human melanocytes depending on the activation of ERK-CREB-MITF-tyrosinase signaling cascades.