sphingosine-phosphorylcholine and Hypopigmentation

Activation of extracellular signal-related kinase (ERK) is involved in decreased melanogenesis by sphingosylphosphorylcholine (SPC). In the present study, we confirmed that SPC activated ERK and that a specific inhibitor of the ERK pathway (PD98059) recovered SPC-induced hypopigmentation. Moreover, we found that SPC significantly reduces protein phosphatase 2A (PP2A) activity in Mel-Ab cells, and that PP2A activator treatment abrogated SPC-induced hypopigmentation. We determined that α-melanocyte-stimulating hormone (α-MSH) increased the expression of dual-specificity phosphatase 6 (DUSP6), an ERK phosphatase, in a time-dependent manner. In contrast, SPC decreased the level of DUSP6 in Mel-Ab cells. Furthermore, inhibiting DUSP6 increased ERK activation and subsequently augmented the SPC-induced hypopigmenting effects. Taken together, our data suggest that SPC-induced phosphatase inhibition is also responsible for the hypopigmentary effects.

Topics: Animals; Cell Line; Dual Specificity Phosphatase 6; Enzyme Activation; Enzyme Activators; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Hypopigmentation; MAP Kinase Signaling System; Melanins; Mice; Phosphorylation; Phosphorylcholine; Protein Phosphatase 2; Protein Processing, Post-Translational; Sphingosine

Sphingosylphosphorylcholine (SPC) acts as a potent lipid mediator and signaling molecule in various cell types. In the present study, we investigated the effects of SPC on melanogenesis and SPC-modulated signaling pathways related to melanin synthesis.. Melanin production was measured in Mel-Ab cells. A luciferase assay was used to detect transcriptional activity of the MITF promoter. Western blot analysis was performed to examine SPC-induced signaling pathways.. SPC produced significant hypopigmentation effects in a dose-dependent manner. It was found that SPC induced not only activation of Akt but also stimulation of mTOR, a downstream mediator of the Akt signaling pathway. Moreover, SPC decreased the levels of LC3 II, which is known to be regulated by mTOR. Treatment with the mTOR inhibitor rapamycin eliminated decreases in melanin and LC3 II levels by SPC. Furthermore, we found that the Akt inhibitor LY294002 restored SPC-mediated downregulation of LC3 II and inhibited the activation of mTOR by SPC.. Our data suggest that the mTOR signaling pathway is involved in SPC-modulated melanin synthesis.

Topics: Analysis of Variance; Animals; Blotting, Western; Cell Line; Chromones; Dose-Response Relationship, Drug; Hypopigmentation; Luciferases; Melanins; Mice; Microscopy, Phase-Contrast; Monophenol Monooxygenase; Morpholines; Phosphorylcholine; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Sphingosine; TOR Serine-Threonine Kinases; Transfection