Pyruvic acid/ethyl pyruvate inhibits melanogenesis in B16F10 melanoma cells through PI3K/AKT, GSK3β, and ROS-ERK signaling pathways

Abstract

Melanin is the main product of human melanocytes and functions to protect skin from ultraviolet (UV) radiation while conferring color to skin and hair. Tyrosinase is the rate-limiting enzyme for melanin synthesis along with tyrosinase-related protein (TRP)-1 and TRP-2. Microphthalmia-associated transcription factor regulates tyrosinase gene expression and is in turn regulated by extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/AKT, and glycogen synthase kinase (GSK)3β signaling pathways. Pyruvic acid (PA) is an energy source for ATP synthesis in the tricarboxylic acid cycle that also acts as a reactive oxygen species (ROS) scavenger. As UV irradiation induces melanin synthesis and ROS generation, we speculated that PA or ethyl pyruvate (EP), a stable form of pyruvate, regulates melanogenesis. B16F10 melanoma cells served as a melanin synthesis model. Treatment with PA or EP suppressed melanin synthesis while increasing intracellular ROS levels, which was accompanied by increased ERK phosphorylation in the case of EP treatment. PA and EP induced GSK3β phosphorylation and activated PI3K/AKT signaling, leading to decreased melanin synthesis. These results indicate that PA and EP inhibit melanogenesis via PI3K/AKT and GSK3β signaling and targeting the ERK and GSK3β pathways, respectively. Thus, PA and EP can potentially be used for treatment of hyperpigmentation disorders.