Nypa fruticans Wurmb inhibits melanogenesis in isobutylmethylxanthine‑treated melanoma via the PI3K/AKT/mTOR/CREB and MAPK signaling pathways

Abstract

Malignant melanoma is responsible for 3.0 and 1.7% of cases of tumor incidence and tumor-associated mortality, respectively, in the Caucasian population. Melanoma is a type of skin cancer that occurs when melanocytes mutate and divide uncontrollably. Nypa fruticans Wurmb (NF) is abundant in phytochemicals (polyphenols and flavonoids) and is traditionally used to treat diseases of the respiratory tract. The present study investigated the inhibitory effect of the ethyl acetate fraction of NF (ENF) on melanogenesis-related factors in isobutylmethylxanthine-treated B16F10 melanoma cells. Phenolics and flavonoids (caffeic acid, catechin, epicatechin and hirsutine) in ENF were analyzed via liquid chromatography-mass spectrometry. In addition, the main factors involved in melanogenesis were identified using immunoblotting, reverse transcription-polymerase chain reaction (RT-PCR), RT-quantitative PCR and immunofluorescence. ENF significantly suppressed the expression of tyrosinase (TYR) and TYR-related proteins 1 and 2 (TYRP-1/2), which are the main factors involved in melanogenesis. ENF also inhibited the expression of microphthalmia-associated transcription factor (MITF) by phosphorylating the related cell signaling proteins (protein kinase B, mammalian target of rapamycin, phosphoinositide 3-kinase and cAMP response element-binding protein). Furthermore, ENF inhibited the phosphorylation of extracellular signal-regulated kinase and thereby downregulated melanogenesis. In conclusion, ENF inhibited melanogenesis by suppressing MITF, which controls TYRP-1/2 and TYR. These results suggested that ENF may be a natural resource that can inhibit excessive melanin expression by regulating various melanogenesis pathways.

A 7-Hydroxy 4-Methylcoumarin Enhances Melanogenesis in B16-F10 Melanoma Cells

“…It has been reported that the activation of the protein kinase AKT mediates the phosphorylation of GSK-3β, which induces melanin synthesis via the upregulation of MITF. In other words, blocking the phosphorylation of AKT triggers the process of melanogenesis [ 17 ]. To investigate whether 7H-4M induces melanogenesis through the AKT signaling pathway in B16-F10 cells, we conducted experiments.…”

Syringetin Promotes Melanogenesis in B16F10 Cells

“…Melanogenic factors are influenced by external stressors and are regulated through cross-regulation involving various signaling molecules. The cAMP signaling pathway has been reported as a regulator of melanogenesis, particularly through the cAMP/PKA/CREB pathway, which activates the expression of genes related to melanogenesis, including MITF, tyrosinase, TRP-1, and TRP-2 [ 17 , 18 ]. In this study, syringetin was found to significantly enhance PKA activity ( Figure 3 ), suggesting that the melanogenic effect of syringetin is mediated via the cAMP/PKA/CREB signaling pathway.…”

“…cAMP is a crucial signal transduction molecule that activates the phosphorylation of PKA, which is one of the primary pathways that stimulates melanogenesis in response to extracellular stimuli. PKA activation then initiates two distinct signaling pathways that upregulate MITF expression: CREB and GSK3 [17,18]. Therefore to investigate the transcription factor that stimulates MITF expression, we examined the phosphorylation levels of PKA, which is the downstream activator of cAMP signaling Figure 3 shows that syringetin treatment significantly upregulated the expression level of phosphorylated PKA in comparison to the control treatment.…”

“…Numerous signaling pathways are involved in melanogenesis, including cAMP-dependent protein kinase A (PKA) and cAMP response element-binding protein (CREB), which stimulate the expression of MITF and lead to an increase in melanin levels [ 17 , 18 ]. The mitogen-activated protein kinase (MAPK) family proteins ERK, JNK, and p38 MAPK also play crucial roles in melanogenesis.…”