Liquiritin and Liquiritigenin Induce Melanogenesis via Enhancement of p38 and PKA Signaling Pathways
Liquiritin and Liquiritigenin Induce Melanogenesis via Enhancement of p38 and PKA Signaling Pathways
复制标题
DOI：
10.3390/medicines6020068
复制
发表时间：
2019-06
期刊：
影响因子：
--
通讯作者：
T. Uto;Tomoe Ohta;Akihisa Yamashita;Shunsuke Fujii;Y. Shoyama
中科院分区：
文献类型：
--
作者：
T. Uto;Tomoe Ohta;Akihisa Yamashita;Shunsuke Fujii;Y. Shoyama
背景：甘草素(Liquiritin，LQ)及其苷元甘草素是甘草中的主要黄酮类化合物。我们的初步筛选确定了LQ和LQG，它们促进黑色素瘤细胞中黑色素的合成。本研究探讨了LQ和LQG激活黑素合成的分子机制。方法：采用小鼠黑色素瘤细胞株(B16-F1)和人黑色素瘤细胞株(HMVII)，分别用LQ和LQG处理。培养后检测黑素含量、细胞内酪氨酸酶活性和细胞存活率。用Western blotting检测蛋白质水平。结果：LQ和LQG能促进黑素合成和细胞内酪氨酸酶活性。LQG诱导的黑色素生成和细胞内酪氨酸酶活性均高于LQ。LQ和LQG诱导酪氨酸酶、酪氨酸酶相关蛋白(TRP)-1和TRP-2的表达。LQ和LQG还可促进小眼球相关转录因子(MITF)的表达和环磷酸腺苷反应元件结合蛋白(CREB)的磷酸化。LQ或LQG可显著增加p38和细胞外信号调节蛋白激酶(ERK)的磷酸化，而对Akt无明显影响。此外，p38抑制剂(SB203580)和蛋白激酶A(PKA)抑制剂(H-89)可部分阻断LQ或LQG介导的黑素合成，而ERK(MEK)抑制剂(U0126)和磷脂酰肌醇-3-激酶(PI3K)抑制剂(LY294002)则无此作用。结论：LQ和LQG通过上调p38和PKA信号通路激活的黑素生成酶的表达，促进MITF的表达和CREB的磷酸化，从而促进黑素合成。
Background: Liquiritin (LQ) and its aglycone, liquiritigenin (LQG), are major flavonoids in licorice root (Glycyrrhiza spp.). Our preliminary screening identified LQ and LQG, which promote melanin synthesis in the melanoma cells. In this study, we investigated the molecular mechanism of melanin synthesis activated by LQ and LQG. Methods: Murine (B16-F1) and human (HMVII) melanoma cell lines were treated with LQ or LQG. After incubation, melanin contents, intracellular tyrosinase activity, and cell viability were evaluated. Protein levels were determined using Western blotting. Results: LQ and LQG activated melanin synthesis and intracellular tyrosinase activity. The induction of melanin and intracellular tyrosinase activity by LQG was higher than that by LQ. LQ and LQG induced the expression of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. LQ and LQG also enhanced microphthalmia-associated transcription factor (MITF) expression, and cyclic AMP-responsive element-binding protein (CREB) phosphorylation. The phosphorylation of p38 and extracellular signal-regulated kinase (ERK), but not Akt, was significantly increased by LQ or LQG. Furthermore, LQ- or LQG-mediated melanin synthesis was partially blocked by p38 inhibitor (SB203580) and protein kinase A (PKA) inhibitor (H-89); however, ERK kinase (MEK) inhibitor (U0126) and phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002) had no effect. Conclusions: The results suggest that LQ and LQG enhance melanin synthesis by upregulating the expression of melanogenic enzymes, which were activated by p38 and PKA signaling pathways, leading to MITF expression and CREB phosphorylation.