title: Anti-melanogenic effects of δ-tocotrienol are associated with tyrosinase-related proteins and MAPK signaling pathway in B16 melanoma cells.
abstract: Tocotrienols are known to possess potent antioxidant, anticancer, and cholesterol lowering activities. Being able to rapidly penetrate the skin, these vitamin E isoforms have been explored for potential treatment against melanoma. This study aimed to elucidate the mechanism involved in the anti-melanogenic effects of δ-tocotrienol (δT3) in B16 melanoma cells. Results showed that at 20 μM of δT3 significantly inhibited melanin formation and ROS generation. Treatment with δT3 also effectively suppressed the expression of melanogenesis-related proteins, including MC1R, MITF, TYRP-1, and TYRP-2. More importantly, we observed that the mitogen-activated protein kinase (MAPK) pathway was involved in mediating δT3's inhibitory effect against melanin production. Specifically, δT3 treatment markedly induced the activation of extracellular signal-regulated kinases (ERK). The use of ERK activation inhibitor (PD98059) abrogated the δT3-mediated downregulation expression melanogenesis-related proteins and restored melanin production. Furthermore, siRNA targeting ERK effectively blocked the δT3-induced repression of tyrosinase and TYRP-1 expression. These results suggest that δT3's inhibitory effect against melanogenesis is mediated by the activation of ERK signaling, thereby resulting in downstream repression of melanogenesis-related proteins and the subsequent melanin production. These data provide insight to δT3's effect and the targeting of ERK signaling for treatment against melanogenesis.
authors.affiliation: Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan.
authors.forename: Lean-Teik
authors.initials: LT
authors.lastname: Ng
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Liang-Tzung
authors.initials: LT
authors.lastname: Lin
authors.affiliation: Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Chiu-Lan
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Nutritional Health, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Hsiu-Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Department of Nutritional Health, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan. Electronic address: wsj268@mail.chna.edu.tw.
authors.forename: Shu-Jing
authors.initials: SJ
authors.lastname: Wu
authors.affiliation: Faculty of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: aalin@kmu.edu.tw.
authors.forename: Chun-Ching
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008543:Melanins / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D005419:Flavonoids; D007211:Indoles; C497234:MITF protein, human; D008543:Melanins; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C009904:melanogen; D014810:Vitamin E; C082097:tocotrienol, delta; D010088:Oxidoreductases; C489799:TYRP1 protein, human; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: ERK activation; MAPK; Melanogenesis; Tocotrienols; Tyrosinase