Protocatechuic Aldehyde Inhibits α-MSH-Induced Melanogenesis in B16F10 Melanoma Cells via PKA/CREB-Associated MITF Downregulation.

Seok-Chun Ko,Seung-Hong Lee

doi:10.3390/ijms22083861

Abstract

Protocatechuic aldehyde (PA) is a naturally occurring phenolic compound that is a potent inhibitor of mushroom tyrosinase. However, the molecular mechanisms of the anti-melanogenesis activity of PA have not yet been reported. The aim of the current study was to clarify the melanogenesis inhibitory effects of PA and its molecular mechanisms in murine melanoma cells (B16F10). We first predicted the 3D structure of tyrosinase and used a molecular docking algorithm to simulate binding between tyrosinase and PA. These molecular modeling studies calculated a binding energy of −527.42 kcal/mol and indicated that PA interacts with Cu400 and 401, Val283, and His263. Furthermore, PA significantly decreased α-MSH-induced intracellular tyrosinase activity and melanin content in a dose-dependent manner. PA also inhibited key melanogenic proteins such as tyrosinase, tyrosinase-related protein 1 (TRP-1), and TRP-2 in α-MSH-stimulated B16F10 cells. In addition, PA decreased MITF expression levels by inhibiting phosphorylation of cAMP response element-binding protein (CREB) and cAMP-dependent protein kinase A (PKA). These results demonstrate that PA can effectively suppress melanin synthesis in melanoma cells. Taken together, our results show that PA could serve as a potential inhibitor of melanogenesis, and hence could be explored as a possible skin-lightening agent.

Highlights

Melanin is produced by melanocytes distributed in the basal layer of the epidermis, and is a key element of skin, hair, and eye color
To further understand the mechanisms involved in the regulation of Microphthalmia-associated transcription factor (MITF) expression by Protocatechuic aldehyde (PA), we investigated whether PA could influence cAMP response element-binding protein (CREB)/protein kinase A (PKA)-mediated signaling pathways in α-melanocyte stimulating hormone (α-MSH)-stimulated B16F10 cells
We first performed a study of PA docking at the active site of mushroom tyrosinase to understand the mechanism underlying the interaction between tyrosinase and PA

Summary

Introduction

Melanin is produced by melanocytes distributed in the basal layer of the epidermis, and is a key element of skin, hair, and eye color. Tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-2, play critical roles in melanogenesis [1,2]. Microphthalmia-associated transcription factor (MITF) is an essential factor that regulates the transcription of the key melanogenic proteins [3]. Activation of both the cAMP-dependent protein kinase A (PKA) and cAMP response element-binding protein (CREB) signaling pathways is known to play an essential role in MITF expression and activity. Downregulation of PKA and CREB signaling in melanocytes inhibits melanin synthesis by downregulating MITF expression

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