Faculty of Biotechnology, College of Applied Life Sciences, SARI, Jeju National University, Jeju 63243, Republic of Korea; Subtropical Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Republic of Korea.
Faculty of Biotechnology, College of Applied Life Sciences, SARI, Jeju National University, Jeju 63243, Republic of Korea; Subtropical Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Republic of Korea.
Chem Biol Interact. 2018 Apr 25;286:132-140. doi: 10.1016/j.cbi.2018.02.033. Epub 2018 Feb 24.
Phytol (3,7,11,15-tetramethyl-2-hexadecen-1-ol) is an acyclic monounsaturated diterpene alcohol generated from chlorophyll metabolism that exerts anti-inflammatory, antithrombotic, antimicrobial, and antitumor effects. However, the effect of phytol on melanogenesis and the underlying molecular mechanisms of its inhibition remain unknown. Here, we found that phytol suppressed α-melanocyte-stimulating hormone-induced melanogenesis in B16F10 murine melanoma cells without any toxic effects. Phytol significantly attenuated melanin production by reducing the expression of tyrosinase and tyrosinase related protein 1. Treatment with phytol inhibited the expression of microphthalmia-associated transcription factor (MITF) by phosphorylating extracellular signal-regulated protein kinase (ERK). The ERK inhibitor PD98059 restored MITF expression and prevented the anti-melanogenic effect of phytol. We found that the ERK inhibitor coincidently abrogated MITF ubiquitination and degradation, suggesting that the ERK pathway is involved in phytol-induced ubiquitination of MITF. Furthermore, our data show that reactive oxygen species (ROS) production was increased in cells treated with phytol. Consistently, a ROS scavenger inhibited ERK phosphorylation and restored MITF degradation. Accordingly, the intermediary role of ROS was confirmed in phytol-induced MITF degradation. Taken together, these results demonstrate that phytol stimulates ROS production and modulates ERK-mediated proteasomal degradation of MITF in B16F10 murine melanoma cells. These findings suggest that phytol may have potential to be utilized as a whitening agent in cosmetics and as a therapy for skin hyperpigmentation.
植物醇（3,7,11,15-四甲基-2-十六碳烯-1-醇）是一种从叶绿素代谢中产生的非环单不饱和二萜醇，具有抗炎、抗血栓、抗菌和抗肿瘤作用。然而，植物醇对黑色素生成的影响及其抑制作用的潜在分子机制尚不清楚。在这里，我们发现植物醇在没有任何毒性作用的情况下抑制 α-促黑色素细胞激素诱导的 B16F10 小鼠黑色素瘤细胞中的黑色素生成。植物醇通过降低酪氨酸酶和酪氨酸酶相关蛋白 1 的表达显著减少黑色素的产生。用植物醇处理可通过磷酸化细胞外信号调节蛋白激酶（ERK）来抑制小眼畸形相关转录因子（MITF）的表达。ERK 抑制剂 PD98059 恢复了 MITF 的表达，并阻止了植物醇的抗黑色素生成作用。我们发现 ERK 抑制剂同时消除了 MITF 的泛素化和降解，表明 ERK 途径参与了植物醇诱导的 MITF 泛素化。此外，我们的数据表明，用植物醇处理的细胞中活性氧（ROS）的产生增加。一致地，ROS 清除剂抑制了 ERK 磷酸化并恢复了 MITF 的降解。因此，在植物醇诱导的 MITF 降解中证实了 ROS 的中间作用。总之，这些结果表明，植物醇刺激 ROS 的产生，并调节 B16F10 小鼠黑色素瘤细胞中 ERK 介导的 MITF 蛋白酶体降解。这些发现表明，植物醇可能有潜力作为化妆品中的美白剂和皮肤色素沉着过度的治疗剂。
