Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
FEBS Open Bio. 2014 Feb 22;4:229-39. doi: 10.1016/j.fob.2014.02.009. eCollection 2014.
Ursolic acid (3β-hydroxy-urs-12-en-28-oic acid) is a natural pentacyclic triterpenoid that is present in many plants, including medicinal herbs, and foods. Ursolic acid was initially identified as an inhibitor of the expression of intercellular adhesion molecule-1 (ICAM-1) in response to interleukin-1α (IL-1α). We report here a novel biological activity: ursolic acid inhibits intracellular trafficking of proteins. Ursolic acid markedly inhibited the IL-1α-induced cell-surface ICAM-1 expression in human cancer cell lines and human umbilical vein endothelial cells. By contrast, ursolic acid exerted weak inhibitory effects on the IL-1α-induced ICAM-1 expression at the protein level. Surprisingly, we found that ursolic acid decreased the apparent molecular weight of ICAM-1 and altered the structures of N-linked oligosaccharides bound to ICAM-1. Ursolic acid induced the accumulation of ICAM-1 in the endoplasmic reticulum, which was linked mainly to high-mannose-type glycans. Moreover, in ursolic-acid-treated cells, the Golgi apparatus was fragmented into pieces and distributed over the cells. Thus, our results reveal that ursolic acid inhibits intracellular trafficking of proteins and induces the accumulation of ICAM-1 linked to high-mannose-type glycans in the endoplasmic reticulum.
熊果酸（3β-羟基-熊-12-烯-28-酸）是一种天然五环三萜类化合物，存在于许多植物中，包括草药和食品。熊果酸最初被鉴定为白细胞介素-1α（IL-1α）反应中细胞间黏附分子-1（ICAM-1）表达的抑制剂。我们在这里报告一种新的生物学活性：熊果酸抑制蛋白质的细胞内运输。熊果酸显著抑制人癌细胞系和人脐静脉内皮细胞中 IL-1α 诱导的细胞表面 ICAM-1 表达。相比之下，熊果酸对 IL-1α 诱导的 ICAM-1 表达在蛋白质水平上仅表现出微弱的抑制作用。令人惊讶的是，我们发现熊果酸降低了 ICAM-1 的表观分子量，并改变了与 ICAM-1 结合的 N-连接寡糖的结构。熊果酸诱导 ICAM-1 在细胞内质网中积累，主要与高甘露糖型糖基有关。此外，在熊果酸处理的细胞中，高尔基体被片段化为小块并分布在细胞中。因此，我们的结果表明，熊果酸抑制蛋白质的细胞内运输，并诱导与内质网中高甘露糖型糖基结合的 ICAM-1 积累。
