Department of Bio and Fermentation Convergence Technology, BK21 PLUS Program, Kookmin University, Seoul 136-702, Korea.
College of Pharmacy, Yanbian University, Yanji 133002, China.
Mar Drugs. 2020 Apr 13;18(4):210. doi: 10.3390/md18040210.
Dysregulation of the Wnt/β-catenin signaling pathway is involved in the development of human hepatocellular carcinoma and has thus emerged as a therapeutic target for this malignant tumor. In this study, we employed sensitive cell-based assays to identify aplykurodin A isolated from as an antagonist of Wnt/β-catenin signaling. Aplykurodin A inhibited β-catenin responsive transcription, which was stimulated by a Wnt3a-conditioned medium or a glycogen synthase kinase 3β inhibitor by accelerating intracellular β-catenin degradation. Aplykurodin A downregulated the level of oncogenic β-catenin and decreased the expression of β-catenin-dependent gene, leading to inhibition of human hepatoma Hep3B and SNU475 cell proliferation. Moreover, apoptosis and autophagy were elicited by aplykurodin A, as indicated by an increase the number of Annexin V-FITC-stained cells and the formation of microtubule-associated protein 1 light chain 3 puncta, respectively, in Hep3B and SNU475 cells. Our findings suggest that aplykurodin A provides a novel therapeutic strategy for human hepatocellular carcinoma via stimulation of oncogenic β-catenin degradation.
Wnt/β-catenin 信号通路的失调参与了人类肝细胞癌的发展，因此成为这种恶性肿瘤的治疗靶点。在这项研究中，我们采用了敏感的基于细胞的测定法，鉴定出从 中分离得到的 aplykurodin A 是 Wnt/β-catenin 信号的拮抗剂。Aplykurodin A 通过加速细胞内 β-catenin 降解来抑制由 Wnt3a 条件培养基或糖原合成激酶 3β 抑制剂刺激的 β-catenin 反应性转录。Aplykurodin A 下调致癌性 β-catenin 的水平，并降低 β-catenin 依赖性基因的表达，从而抑制人肝癌 Hep3B 和 SNU475 细胞的增殖。此外，aplykurodin A 诱导线粒体相关蛋白 1 轻链 3 点状形成和 Annexin V-FITC 染色细胞数量的增加，分别在 Hep3B 和 SNU475 细胞中引起细胞凋亡和自噬。我们的研究结果表明，aplykurodin A 通过刺激致癌性 β-catenin 降解为人类肝细胞癌提供了一种新的治疗策略。
