title: Caffeic acid phenethyl ester inhibits alpha-melanocyte stimulating hormone-induced melanin synthesis through suppressing transactivation activity of microphthalmia-associated transcription factor.
abstract: Caffeic acid phenethyl ester (1), a natural compound found in various plants and propolis, is a well-known anti-inflammatory, immunomodulatory, and cytotoxic agent. The present study aimed to investigate the molecular events underlying the antimelanogenic activity of 1 in alpha-melanocyte stimulating hormone (α-MSH)-stimulated B16-F10 melanoma cells. In this investigation, 1 effectively reduced α-MSH-stimulated melanin synthesis by suppressing expression of melanogenic enzymes such as tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2), although this compound did not directly inhibit tyrosinase enzyme activity. On the other hand, the expression and nuclear translocation of microphthalmia-associated transcription factor (MITF) as a key transcription factor for tyrosinase expression regulating melanogenesis were not affected by treatment with 1. The upstream signaling pathways including cAMP response element-binding protein (CREB), glycogen synthase kinase-3β (GSK-3β), and Akt for activation and expression of MITF were also not influenced by 1. Interestingly, 1 inhibited transcriptional activity of a tyrosinase promoter by suppressing the interaction of MITF protein with an M-box containing a CATGTG motif on the tyrosinase promoter. Given the important role of MITF in melanogenesis, suppression of 1 on the function of MITF to transactivate tyrosinase promoter may present a novel therapeutic approach to treat hyperpigmentation disorders.
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University , Yangsan, Gyeongnam, Republic of Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Lee
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Han-Sol
authors.initials: HS
authors.lastname: Jeong
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Ha
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002109:Caffeic Acids / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007370:Interferon Type I; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011257:Pregnancy Proteins; D015533:Transcriptional Activation; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism
chemical_list: D002109:Caffeic Acids; D017362:Cyclic AMP Response Element-Binding Protein; D007370:Interferon Type I; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D011257:Pregnancy Proteins; C020947:interferon tau; D007980:Levodopa; D000521:alpha-MSH; D010088:Oxidoreductases; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol