Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, I-95123 Catania, Italy.
Sooft Italia S.p.A., Rome, Italy.
Int J Mol Med. 2017 Oct;40(4):1277-1284. doi: 10.3892/ijmm.2017.3104. Epub 2017 Aug 23.
The mechanisms underlying cutaneous melanogenesis have been widely studied; however, very little is known about uveal melanogenesis. Melanin is normally produced by uveal melanocytes and gives the color to the iris. A derangement from this normal production may occur, for instance, by iatrogenic events, such as glaucoma therapy with prostaglandins that may enhance cutaneous and iris pigmentation. In this study, we investigated the mechanisms that regulate uveal melanogenesis in human uveal melanoma cells (92.1) and murine cutaneous melanoma cells (B16-F1). In the first part of the study, we compared the effects of known cutaneous pigmenting agents on the B16-F1 and 92.1 cells, showing an opposite response of the two cell lines. Subsequently, using argan oil, a known depigmenting agent for murine cutaneous melanoma cells, on 92.1 cells, we found that in these cells, it also functioned as an inhibitor of melanogenesis and tyrosinase expression. From a molecular perspective, treatment of the 92.1 cells with argan oil decreased melanogenesis-associated transcription factor (MITF) gene expression by inducing MITF phosphorylation at Ser73, thus leading to MITF ubiquitination and disposal. It also led to the downregulation of the extracellular signal-regulated kinase (ERK)1/2 and Akt pathways, also known to be involved in cutaneous melanogenesis, although with an opposing function. Taken together, our data indicate that: ⅰ) some differences exist in the regulation of melanogenesis between cutaneous and uveal melanoma cells; and ⅱ) argan oil exerts a depigmenting effect on 92.1 cells through its action on the ERK1/2 and Akt pathways.
皮肤黑色素生成的机制已得到广泛研究；然而，关于葡萄膜黑色素生成的了解甚少。黑色素通常由葡萄膜黑色素细胞产生，赋予虹膜颜色。这种正常产生可能会发生失调，例如，由于医源性事件，如前列腺素治疗青光眼，可能会增强皮肤和虹膜色素沉着。在这项研究中，我们研究了调节人葡萄膜黑色素瘤细胞（92.1）和鼠皮肤黑色素瘤细胞（B16-F1）中葡萄膜黑色素生成的机制。在研究的第一部分，我们比较了已知的皮肤着色剂对 B16-F1 和 92.1 细胞的影响，显示出两种细胞系的相反反应。随后，使用角鲨烷油，一种已知的鼠皮肤黑色素瘤细胞的褪黑素剂，在 92.1 细胞上，我们发现它也作为黑素生成和酪氨酸酶表达的抑制剂。从分子角度来看，用角鲨烷油处理 92.1 细胞通过诱导 MITF 在丝氨酸 73 处磷酸化，从而导致 MITF 泛素化和处置，降低与黑色素生成相关的转录因子（MITF）基因表达。它还导致细胞外信号调节激酶（ERK1/2）和 Akt 通路的下调，这些通路也已知参与皮肤黑色素生成，尽管具有相反的功能。总之，我们的数据表明：i）皮肤和葡萄膜黑色素瘤细胞之间的黑色素生成调控存在一些差异；ii）角鲨烷油通过作用于 ERK1/2 和 Akt 通路对 92.1 细胞发挥褪黑素作用。
