Department of Biomedical Sciences, Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Ulsan 44610, Korea.
Department of Dermatology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
Molecules. 2022 Aug 25;27(17):5449. doi: 10.3390/molecules27175449.
The dysregulation of melanin production causes skin-disfiguring ultraviolet (UV)-associated hyperpigmented spots. Previously, we found that the activation of c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), inhibited melanogenesis.
We selected BCI-215 as it may modify MAPK expression via a known function of a dual-specificity phosphatase (DUSP) 1/6 inhibitor. B16F10 melanoma cells, Mel-ab cells, human melanocytes, and a coculture were used to assess the anti-melanogenic activity of BCI-215. The molecular mechanisms were deciphered by assaying the melanin content and cellular tyrosinase activity via immunoblotting and RT-PCR.
BCI-215 was found to suppress basal and cAMP-stimulated melanin production and cellular tyrosinase activity in vitro through the downregulation of microphthalmia-associated transcription factor (MITF) protein and its downstream enzymes. The reduction in MITF expression caused by BCI-215 was found to be due to all three types of MAPK activation, including extracellular signal-regulated kinase (ERK), JNK, and p38. The degree of activation was greater in ERK. A phosphorylation of the β-catenin pathway was also demonstrated. The melanin index, expression of MITF, and downstream enzymes were well-reduced in UVB-irradiated ex vivo human skin by BCI-215.
As BCI-215 potently inhibits UV-stimulated melanogenesis, small molecules of DUSP-related signaling modulators may provide therapeutic benefits against pigmentation disorders.
黑色素生成的失调会导致皮肤出现难看的紫外线（UV）相关色素沉着斑。此前，我们发现促分裂原活化蛋白激酶（MAPK）家族中的 c-Jun N-末端激酶（JNK）的激活可抑制黑色素生成。
我们选择 BCI-215，因为它可能通过双特异性磷酸酶（DUSP）1/6 抑制剂的已知功能来调节 MAPK 表达。我们使用 B16F10 黑色素瘤细胞、Mel-ab 细胞、人黑素细胞和共培养物来评估 BCI-215 的抗黑色素生成活性。通过免疫印迹和 RT-PCR 测定黑色素含量和细胞酪氨酸酶活性来解析分子机制。
发现 BCI-215 通过下调小眼畸形相关转录因子（MITF）蛋白及其下游酶来抑制体外基础和 cAMP 刺激的黑色素生成和细胞酪氨酸酶活性。BCI-215 引起的 MITF 表达减少被发现是由于三种类型的 MAPK 激活，包括细胞外信号调节激酶（ERK）、JNK 和 p38。ERK 的激活程度更大。还证明了 β-连环蛋白途径的磷酸化。BCI-215 可显著减少 UVB 照射的离体人皮肤中的黑色素指数、MITF 表达和下游酶。
由于 BCI-215 可强力抑制 UV 刺激的黑色素生成，因此 DUSP 相关信号转导调节剂的小分子可能为色素沉着障碍提供治疗益处。
