Beauvericin inhibits melanogenesis by regulating cAMP/PKA/CREB and LXR-α/p38 MAPK–mediated pathways

Abstract

Melanogenesis is the process of production of melanin pigments that are responsible for the colors of skin, eye, and hair and provide protection from ultraviolet radiation. However, excessive levels of melanin formation cause hyperpigmentation disorders such as freckles, melasma, and age spots. Liver X receptors (LXR) are nuclear oxysterol receptors belonging to the family of ligand-activated transcription factors and physiological regulators of lipid and cholesterol metabolism. In the skin, activation of LXRs stimulates differentiation of keratinocytes and augments lipid synthesis in sebocytes. However, the function of LXRs in melanogenesis has not been clearly elucidated. In addition, although beauvericin, a well-known mycotoxin primarily isolated from several fungi, has various biological properties, its involvement in melanogenesis has not been reported. Therefore, in this study, we examined the effects of beauvericin on melanogenesis and its molecular mechanisms. Beauvericin decreased melanin content and tyrosinase activity without any cytotoxicity. Beauvericin also reduced protein levels of MITF, tyrosinase, TRP1, and TRP2. In addition, beauvericin suppressed cAMP-PKA-CREB signaling and upregulated expression of LXR-α, resulting in the suppression of p38 MAPK. Our results indicate that beauvericin attenuates melanogenesis by regulating both cAMP/PKA/CREB and LXR-α/p38 MAPK pathways, consequently leading to a reduction of melanin levels.

Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G1 Microbial Products against Melanoma Cells

“…In order to find effective natural compounds to treat melanoma, we investigated the cytotoxic effects in A375SM cells and the underlying molecular mechanisms of BEA and BEA G 1 , which are two fungal cyclic hexadepsipeptides. Previous studies have shown that BEA can induce apoptosis in several cancer cells, such as lung cancer, colon cancer, leukemia, and hepatoma cells [10][11][12][13][14]. However, there has been no report regarding the inhibitory activities of BEA and its analogue BEA G 1 against malignant melanoma.…”

“…The bioactive secondary metabolite beauvericin (BEA) was originally isolated from the entomopathogenic fungus Beaveria bassiana [10]. BEA, a cyclic hexadepsipeptide mycotoxin biosynthesized from N-methyl phenylalanine and 2-hydroxyisovaleric acid, is reported to exhibit diverse biological activities, including antimicrobial, insecticidal, antiviral, antiplatelet aggregation, ionophoric, anti-inflammatory, antimelanogenesis, and antitumor effects [11,12]. Mechanistic studies on the cytotoxic effects of BEA have shown that it induced apoptosis in several human cancer cells, such as those derived from the blood, lung, colon, liver, prostate, breast, pancreas, and brain.…”

Melanogenic Effects of Maclurin Are Mediated through the Activation of cAMP/PKA/CREB and p38 MAPK/CREB Signaling Pathways

“…Melanin content was determined as previously described by Lee et al [17]. Briefly, human epidermal melanocytes were treated with maclurin and then washed with PBS, harvested, and subjected to a melanin content assay.…”

“…Maclurin concentration dependently increased both melanin content (Figure 1(b)) and cellular tyrosinase activity (Figure 1(c)) without any cytotoxicity at the concentrations tested (Figure 1(d)). In these experiments, forskolin was introduced as a positive control [17] because it increases both melanin content and cellular tyrosinase activity. In the Fontana-Masson staining and photography analysis, we found that maclurin treatment increased the level of melanin in the reconstructed epidermis (Figure 1(e)).…”

“…Those molecular effects were attenuated by treatment with H89 (a PKA inhibitor) (Figures 2(b)-2(d)). In these experiments, forskolin and H89 were introduced as a positive control and a negative control, respectively [17]. Forskolin increased cAMP production, PKA activity, and CREB phosphorylation, and H89 reduced PKA activity and CREB phosphorylation.…”