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Citric acid promoted melanin synthesis in B16F10 mouse melanoma cells, but inhibited it in human epidermal melanocytes and HMV-II melanoma cells via the GSK3?/?-catenin signaling pathway.

ABSTRACT: Melanin, a pigment synthesized by melanocytes in the skin, resists the damage caused by ultraviolet rays to cells. Citric acid, a well-known food additive, is commonly used as an antioxidant and is an important part of the tricarboxylic acid (TCA) cycle for energy production during cellular metabolism. Here, we aimed to investigate whether the addition of excess citric acid regulates melanin synthesis, and to delineate the underlying mechanism. First, we observed that citric acid exerts opposite redox effects on mouse and human cells. Interestingly, treatment with excess citric acid increased the melanin content in mouse cells but decreased it in human cells. Furthermore, the expression of factors important for melanin synthesis, such as microphthalmia-associated transcription factor (MITF), was also regulated by citric acid treatment-it was promoted in mouse cells and suppressed in human cells. Citric acid also impacted the upstream regulators of MITF, glycogen synthase kinase 3? (GSK3?), and ?-catenin. Second, we determined the importance of GSK3? in the citric acid-mediated regulation of melanin synthesis, using a GSK3? inhibitor (BIO). To the best of our knowledge, this is the first study to show that citric acid regulates melanin synthesis via the GSK3?/?-catenin signaling pathway, and that equal amounts of exogenous citric acid exert opposing effects on mouse and human cells.

SUBMITTER: Zhou S

PROVIDER: S-EPMC7746170 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Citric acid promoted melanin synthesis in B16F10 mouse melanoma cells, but inhibited it in human epidermal melanocytes and HMV-II melanoma cells via the GSK3β/β-catenin signaling pathway.

Zhou Siqi S Sakamoto Kazuichi K

PloS one 20201217 12

Melanin, a pigment synthesized by melanocytes in the skin, resists the damage caused by ultraviolet rays to cells. Citric acid, a well-known food additive, is commonly used as an antioxidant and is an important part of the tricarboxylic acid (TCA) cycle for energy production during cellular metabolism. Here, we aimed to investigate whether the addition of excess citric acid regulates melanin synthesis, and to delineate the underlying mechanism. First, we observed that citric acid exerts opposite ...[more]

PMID: 33332393

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Project description:Skin hyperpigmentation disorders arise due to excessive production of the macromolecular pigment melanin catalyzed by the enzyme tyrosinase. Recently, the therapeutic use of curcumin for inhibiting tyrosinase activity and production of melanin have been recognized, but poor stability and solubility have limited its use, which has inspired synthesis of curcumin analogs. Here, we investigated four novel chemically modified curcumin (CMC) derivatives (CMC2.14, CMC2.5, CMC2.23 and CMC2.24) and compared them to the parent compound curcumin (PC) for inhibition of in vitro tyrosinase activity using two substrates for monophenolase and diphenolase activities of the enzyme and for diminution of cellular melanogenesis. Enzyme kinetics were analyzed using Lineweaver-Burk and Dixon plots and nonlinear curve-fitting to determine the mechanism for tyrosinase inhibition. Copper chelating activity, using pyrocatechol violet dye indicator assay, and antioxidant activity, using a DPPH radical scavenging assay, were also conducted. Next, the capacity of these derivatives to inhibit tyrosinase-catalyzed melanogenesis was studied in B16F10 mouse melanoma cells and the mechanisms of inhibition were elucidated. Inhibition mechanisms were studied by measuring intracellular tyrosinase activity, cell-free and intracellular α-glucosidase enzyme activity, and effects on MITF protein level and cAMP maturation factor. Our results showed that CMC2.24 showed the greatest efficacy as a tyrosinase inhibitor of all the CMCs and was better than PC as well as a popular tyrosinase inhibitor-kojic acid. Both CMC2.24 and CMC2.23 inhibited tyrosinase enzyme activity by a mixed mode of inhibition with a predominant competitive mode. In addition, CMC2.24 as well as CMC2.23 showed a comparable robust efficacy in inhibiting melanogenesis in cultured melanocytes. Furthermore, after removal of CMC2.24 or CMC2.23 from the medium, we could demonstrate a partial recovery of the suppressed intracellular tyrosinase activity in the melanocytes. Our results provide a proof-of-principle for the novel use of the CMCs that shows them to be far superior to the parent compound, curcumin, for skin depigmentation.

Dataset Information

Citric acid promoted melanin synthesis in B16F10 mouse melanoma cells, but inhibited it in human epidermal melanocytes and HMV-II melanoma cells via the GSK3?/?-catenin signaling pathway.

Publications

Citric acid promoted melanin synthesis in B16F10 mouse melanoma cells, but inhibited it in human epidermal melanocytes and HMV-II melanoma cells via the GSK3β/β-catenin signaling pathway.

Similar Datasets

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