The plant sesquiterpene lactone parthenolide inhibits Wnt/β-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1

The Journal of Biological Chemistry
Xiaoliang ZhuLin Li

Abstract

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 b...Continue Reading

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Citations

Nov 13, 2018·Journal of Cellular Physiology·Ghader MolaviElaheh Zadeh Hosseingholi
Aug 15, 2019·Journal of Cellular and Molecular Medicine·Guoqing LiDan Liu
Nov 26, 2019·Natural Product Reports·Robert R A FreundHans-Dieter Arndt
Sep 22, 2020·Science China. Life Sciences
Jul 23, 2018·Natural Products and Bioprospecting·Yue-Mao Shen, Duo-Zhi Chen
Jul 23, 2020·Frontiers in Pharmacology·Wen-Kai YuJiang-Jiang Qin
Jun 21, 2020·Antioxidants·Ekaterina ProshkinaAlexey Moskalev
Sep 22, 2020·Science China. Life Sciences·Yuemao Shen, Xiaojiang Hao
Jan 28, 2020·International Journal of Molecular Medicine·Tengxiang ChenBing Guo
Oct 19, 2020·Journal of Ovarian Research·Jing XuYang Liu
Jan 4, 2021·Natural Products and Bioprospecting·Min HuangJian Ding
Mar 5, 2019·Journal of Natural Products·Yulin RenA Douglas Kinghorn
Dec 9, 2020·Journal of Medicinal Chemistry·Yulin Ren, A Douglas Kinghorn

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