College of Life Science, Northwest Normal University, Lanzhou 730070, China.
Int J Mol Sci. 2020 Apr 30;21(9):3164. doi: 10.3390/ijms21093164.
Leukamenin E is a natural -kaurane diterpenoid isolated from (Hemsl) Hara that has been found to be a novel and potential keratin filament inhibitor, but its underlying mechanisms remain largely unknown. Here, we show that leukamenin E induces keratin filaments (KFs) depolymerization, largely independently of microfilament (MFs) and microtubules (MTs) in well-spread cells and inhibition of KFs assembly in spreading cells. These effects are accompanied by keratin phosphorylation at K8-Ser73/Ser431 and K18-Ser52 via the by extracellular signal-regulated kinases (ERK) pathway in primary liver carcinoma cells (PLC) and human umbilical vein endothelial cells (HUVECs). Moreover, leukamenin E increases soluble pK8-Ser73/Ser431, pK18-Ser52, and pan-keratin in the cytoplasmic supernatant by immunofluorescence imaging and Western blotting assay. Accordingly, leukamenin E inhibits the spreading and migration of cells. We propose that leukamenin E-induced keratin phosphorylation may interfere with the initiation of KFs assembly and block the formation of a new KFs network, leading to the inhibition of cell spreading. Leukamenin E is a potential target drug for inhibition of KFs assembly.
白细胞烯 E 是一种从 （Hemsl）Hara 中分离出来的天然贝壳杉烷二萜，已被发现是一种新型的潜在角蛋白丝抑制剂，但它的潜在机制在很大程度上仍不清楚。在这里，我们表明白细胞烯 E 诱导角蛋白丝（KFs）解聚，这在铺展细胞中在很大程度上独立于微丝（MFs）和微管（MTs），并抑制铺展细胞中 KFs 的组装。这些作用伴随着角蛋白在原发性肝癌细胞（PLC）和人脐静脉内皮细胞（HUVECs）中通过细胞外信号调节激酶（ERK）途径磷酸化 K8-Ser73/Ser431 和 K18-Ser52。此外，白细胞烯 E 通过免疫荧光成像和 Western blot 分析增加细胞质上清液中可溶性 pK8-Ser73/Ser431、pK18-Ser52 和泛角蛋白。因此，白细胞烯 E 抑制细胞的铺展和迁移。我们提出，白细胞烯 E 诱导的角蛋白磷酸化可能干扰 KFs 组装的起始，并阻止新的 KFs 网络的形成，从而抑制细胞的铺展。白细胞烯 E 是抑制 KFs 组装的潜在靶标药物。
