Low-dose imiquimod induces melanogenesis in melanoma cells through an ROS-mediated pathway

IF 3.8 3区 医学 Q1 DERMATOLOGY Journal of dermatological science Pub Date : 2023-12-22 DOI:10.1016/j.jdermsci.2023.12.005
Zheng-Yi Li, Shu-Hao Chang, Kuang-Ting Liu, Alaina Edelie Wu, Chien-Sheng Hsu, Shi-Wei Huang, Mu-Chi Chung, Shih-Chung Wang, Jun-Kai Kao, Yi-Ju Chen, Jeng-Jer Shieh
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Abstract

Background

Melanogenesis is the process of melanin maturation which not only protects skin from UV radiation but also plays an important role in antigenicity of melanomas. Imiquimod (IMQ) is a toll-like receptor 7 (TLR7) agonist that exhibits antiviral and anticancer activity.

Objective

To explore whether IMQ could induce melanogenesis in melanoma cells.

Methods

The mouse melanoma cell line B16F10, the mouse immortalized melanocyte Melan-A, and human melanoma cell lines MNT-1, C32 and A375 were utilized in this study. The pigmented level was observed by the centrifuged cell pellet. The intracellular and extracellular melanin levels were examined in the absorbance in NaOH-extracted cell lysate and cell-cultured medium, respectively. The expression of melanogenesis related proteins was examined by immunoblotting. The intracellular cyclic AMP amount was evaluated by the cAMP Glo assay kit. The activity of phosphodiesterase 4B (PDE4B) was investigated by CREB reporter assay with overexpressed PDE4B or not.

Results

We demonstrated that a low dose of IMQ could trigger melanogenesis in B16F10 cells. IMQ induced microphthalmia-associated transcription factor (MITF) nuclear translocation, upregulated the expression of melanogenesis-related proteins, increased tyrosinase (TYR) activity, and led to pigmentation in B16F10 cells. Next, we found that IMQ-induced melanogenesis was activated by excessive intracellular cAMP accumulation, which was regulated through IMQ-mediated PDE4B inhibition. Finally, IMQ-induced ROS production was found to be involved in melanogenesis by its control of PDE4B activity.

Conclusions

Low dose of IMQ could activate melanogenesis through the ROS/PDE4B/PKA pathway in melanoma cells.

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低剂量咪喹莫特通过 ROS 介导的途径诱导黑色素瘤细胞的黑色素生成
背景黑色素生成是黑色素成熟的过程,它不仅能保护皮肤免受紫外线辐射,还在黑色素瘤的抗原性方面发挥着重要作用。方法 本研究利用小鼠黑色素瘤细胞系B16F10、小鼠永生黑色素细胞Melan-A以及人黑色素瘤细胞系MNT-1、C32和A375。色素水平通过离心后的细胞团进行观察。细胞内和细胞外黑色素水平分别通过 NaOH 提取的细胞裂解液和细胞培养培养基的吸光度进行检测。用免疫印迹法检测黑色素生成相关蛋白的表达。细胞内环磷酸腺苷的含量由 cAMP Glo 检测试剂盒进行评估。结果我们证明,低剂量的IMQ可诱导B16F10细胞的黑色素生成。IMQ诱导小眼球相关转录因子(MITF)核转位,上调黑色素生成相关蛋白的表达,增加酪氨酸酶(TYR)活性,导致B16F10细胞色素沉着。接着,我们发现 IMQ 诱导的黑色素生成是由细胞内过量的 cAMP 积累激活的,而这种积累是通过 IMQ 介导的 PDE4B 抑制来调节的。结论低剂量 IMQ 可通过黑色素瘤细胞中的 ROS/PDE4B/PKA 通路激活黑色素生成。
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来源期刊
Journal of dermatological science
Journal of dermatological science 医学-皮肤病学
CiteScore
7.60
自引率
2.20%
发文量
98
审稿时长
9.1 weeks
期刊介绍: Although the Journal is the official organ of the Japanese Society for Investigative Dermatology, it serves as an international forum for the work of all dermatological scientists. With an internationally renowned Editorial Board, the Journal maintains high scientific standards in the evaluation and publication of manuscripts. The Journal also publishes invited reviews, commentaries, meeting announcements and book reviews. Letters to the Editor reporting new results or even negative scientific data, if they contribute to advances in dermatology are encouraged. Letters to the Editor should be less than 1000 words with up to 2 figures or tables.
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