Inhibitory effects of N,N,N-trimethyl phytosphingosine-iodide on melanogenesis via ERK activation-mediated MITF degradation.
N,N,N-trimethyl phytosphingosine-iodide (TMP) was recently developed as an antitumor agent. We examined the effects of TMP on melanogenesis and its related signaling pathways in normal human melanocytes. Our results showed that melanin is significantly reduced in a dose-dependent manner in both cells following liposomal TMP treatment. We also investigated changes in the phosphorylation of extracellular signal-regulated kinase (ERK), which is related to the degradation of microphthalmia-associated transcription factor (MITF). Our results indicated that liposomal TMP treatment leads to the phosphorylation of ERK, which reduces both MITF and tyrosinase protein levels. Treatment with PD98059, an ERK pathway-specific inhibitor, restored liposomal TMP-induced reductions in melanin, abrogated reductions in tyrosinase activity, and downregulated MITF and tyrosinase protein. In conclusion, these results suggest that the inhibitory effects of TMP on melanogenesis are due to MITF and tyrosinase downregulation via ERK activation.
a Department of Dermatology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea.
Woo Jin
WJ
Lee
a Department of Dermatology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea.
Seunghyun
S
Bang
b Department of Dermatology, Kangnam Sacred Heart Hospital , College of Medicine, Hallym University , Seoul , Korea.
Bo Young
BY
Chung
c Department of Life Sciences, Division of Life and Pharmaceutical Sciences and the Research Center for Cellular Homeostasis , Ewha Womans University , Seoul , Korea.
Hyejung
H
Jung
a Department of Dermatology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea.
Eok Soo
ES
Oh
a Department of Dermatology, Asan Medical Center , University of Ulsan College of Medicine , Seoul , Korea.
Sung Eun
SE
Chang
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004339:Drug Compounding; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008543:Melanins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D005419:Flavonoids; D008081:Liposomes; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; C577077:N,N,N-trimethylphytosphingosine; D047428:Protein Kinase Inhibitors; D000644:Quaternary Ammonium Compounds; D014442:Monophenol Monooxygenase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013110:Sphingosine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
extracellular signal-regulated kinase; melanogenesis; microphthalmia-associated transcription factor; phytosphingosine