The plant sesquiterpene lactone parthenoide inhibits Wnt/{beta}-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1 [Protein Synthesis and Degradation]

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 parthenoide (PTL), a sesquiterpene lactone, inhibits Wnt signaling. We found that PTL dose-dependently inhibits Wnt3a- and CHIR-induced transcriptional activity assessed with the T-cell factor/lymphoid enhancer factor(TCF/LEF)-firefly luciferase (TOPFlash) assay in HEK293 cells. Further investigations revealed that PTL decreases 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 that 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.

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