From the State Key Laboratory of Molecular Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Networks, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
the State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
J Biol Chem. 2018 Apr 6;293(14):5335-5344. doi: 10.1074/jbc.M117.819300. Epub 2018 Feb 9.
The Wnt/β-catenin pathway is essential for embryonic development and homeostasis, but excessive activation of this pathway is frequently observed in various human diseases, including cancer. Current therapeutic drugs targeting the Wnt pathway often lack sufficient efficacy, and new compounds targeting this pathway are therefore greatly needed. Here we report that the plant-derived natural product parthenolide (PTL), a sesquiterpene lactone, inhibits Wnt signaling. We found that PTL dose-dependently inhibits Wnt3a- and CHIR99021-induced transcriptional activity assessed with the T-cell factor (TCF)/lymphoid enhancer factor (LEF) firefly luciferase (TOPFlash) assay in HEK293 cells. Further investigations revealed that PTL decreases the levels of the transcription factors TCF4/LEF1 without affecting β-catenin stability or subcellular distribution. Moreover, this effect of PTL on TCF4/LEF1 was related to protein synthesis rather than to proteasome-mediated degradation. Of note, siRNA-mediated knockdown of RPL10, a ribosome protein PTL binds, substantially decreased TCF4/LEF1 protein levels and also Wnt3a-induced TOPFlash activities, suggesting a potential mechanism by which PTL may repress Wnt/β-catenin signaling. In summary, PTL binds RPL10 and thereby potently inhibits the Wnt/β-catenin pathway.
Wnt/β-连环蛋白通路对于胚胎发育和内稳态至关重要，但在各种人类疾病中，包括癌症，经常观察到该通路的过度激活。目前针对 Wnt 通路的治疗药物往往缺乏足够的疗效，因此非常需要针对该通路的新化合物。在这里，我们报告植物来源的天然产物小白菊内酯（PTL），一种倍半萜内酯，可抑制 Wnt 信号通路。我们发现 PTL 以剂量依赖性方式抑制 Wnt3a 和 CHIR99021 诱导的转录活性，通过 T 细胞因子（TCF）/淋巴增强因子（LEF）萤火虫荧光素酶（TOPFlash）测定法在 HEK293 细胞中进行评估。进一步的研究表明，PTL 降低了转录因子 TCF4/LEF1 的水平，而不影响 β-连环蛋白的稳定性或亚细胞分布。此外，PTL 对 TCF4/LEF1 的这种作用与蛋白质合成有关，而不是与蛋白酶体介导的降解有关。值得注意的是，PTL 结合的核糖体蛋白 RPL10 的 siRNA 介导的敲低，大大降低了 TCF4/LEF1 蛋白水平，并且还降低了 Wnt3a 诱导的 TOPFlash 活性，这表明 PTL 可能抑制 Wnt/β-连环蛋白信号的潜在机制。总之，PTL 结合 RPL10 并因此强烈抑制 Wnt/β-连环蛋白通路。
