Inhibitory effects of N,N,N-trimethyl phytosphingosine-iodide on melanogenesis via ERK activation-mediated MITF degradation

Abstract

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.

Graphical abstract

Liposomal TMP treatment decreases the expression of both MITF and tyrosinase proteins

Key words:

• melanogenesis
• phytosphingosine
• extracellular signal-regulated kinase
• microphthalmia-associated transcription factor

Acknowledgments

We thank Dr. Myeong Jun Choi (Kyunggi University, Suwon, Korea) for the gift of L-TMP.

Notes

Abbreviations: ANOVA, Analysis of variance; cAMP/PKA, cyclic adenosine monophosphate/protein kinase A; DOPA, dihydroxyphenylalanine; ERK, extracellular signal-regulated kinase; L-TMP, liposomal TMP; MITF, microphthalmia-associated transcription factor; MSH, melanocyte-stimulating hormone; NHM, normal human melanocyte; p38 MAPK, p38 mitogen-activated protein kinase; PBS, phosphate-buffered saline; PI3K/Akt, phosphoinositide 3-kinase/Akt; PKC, protein kinase C; SDS–PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; TMP, trimethyl phytosphingosine-iodide; TRP-1, tyrosinase-related protein; TRP-2, tyrosinase-related protein 2; WST, water-soluble tetrazolium salt.