Jiang Shiyou, Du Jiacheng, Kong Qinghua, Li Chaocui, Li Yan, Sun Handong, Pu Jianxin, Mao Bingyu
State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
PLoS One. 2015 Oct 6;10(10):e0139830. doi: 10.1371/journal.pone.0139830. eCollection 2015.
The Hedgehog (Hh) signaling pathway plays important roles in the tumorigenesis of multiple cancers and is a key target for drug discovery. In a screen of natural products extracted from Chinese herbs, we identified eight ent-Kaurane diterpenoids and two triterpene dilactones as novel Hh pathway antagonists. Epistatic analyses suggest that these compounds likely act at the level or downstream of Smoothened (Smo) and upstream of Suppressor of Fused (Sufu). The ent-Kauranoid-treated cells showed elongated cilia, suppressed Smo trafficking to cilia, and mitotic defects, while the triterpene dilactones had no effect on the cilia and ciliary Smo. These ent-Kaurane diterpenoids provide new prototypes of Hh inhibitors, and are valuable probes for deciphering the mechanisms of Smo ciliary transport and ciliogenesis.
刺猬（Hh）信号通路在多种癌症的肿瘤发生中起重要作用，是药物研发的关键靶点。在对从中药中提取的天然产物进行的筛选中，我们鉴定出8种对映-贝壳杉烷二萜和2种三萜双内酯为新型Hh通路拮抗剂。上位性分析表明，这些化合物可能作用于平滑（Smo）蛋白的水平或下游以及融合抑制因子（Sufu）的上游。经对映-贝壳杉烷类化合物处理的细胞显示出纤毛伸长、Smo蛋白向纤毛的转运受到抑制以及有丝分裂缺陷，而三萜双内酯对纤毛和纤毛中的Smo蛋白没有影响。这些对映-贝壳杉烷二萜提供了Hh抑制剂的新原型，并且是用于解读Smo蛋白纤毛运输和纤毛发生机制的有价值的探针。
