The plant sesquiterpene lactone parthenolide inhibits Wnt/-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1
Zhu, Xiaoliang1; Yuan, Chunmao2; Tian, Chenyang1,4; Li, Chen5; Nie, Fen1; Song, Xiaomin1; Zeng, Rong5; Wu, Dianqing6,7; Hao, Xiaojiang2,3; Li, Lin1,4
2018-04-06
Source PublicationJOURNAL OF BIOLOGICAL CHEMISTRY
ISSN0021-9258
Volume293Issue:14Pages:5335-5344
AbstractThe Wnt/-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 -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/-catenin signaling. In summary, PTL binds RPL10 and thereby potently inhibits the Wnt/-catenin pathway.
KeywordInhibitor Protein Synthesis Small Molecule T-cell Factor (Tcf) Wnt Signaling
DOI10.1074/jbc.M117.819300
Language英语
WOS IDWOS:000429409300036
Citation statistics
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/60501
Collection植物化学与西部植物资源持续利用国家重点实验室
Affiliation1.Chinese Acad Sci, State Key Lab Mol Biol, Ctr Excellence Mol Cell Sci,Shanghai Inst Biol Sc, Innovat Ctr Cell Signaling Networks,Inst Biochem, Shanghai 200031, Peoples R China
2.Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Guiyang 550014, Guizhou, Peoples R China
3.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650204, Yunnan, Peoples R China
4.Shanghai Tech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China
5.Chinese Acad Sci, Ctr Excellence Mol Cell Sci, Inst Biochem & Cell Biol, Key Lab Syst Biol,Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China
6.Yale Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA
7.Yale Sch Med, Dept Pharmacol, New Haven, CT 06520 USA
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Zhu, Xiaoliang,Yuan, Chunmao,Tian, Chenyang,et al. The plant sesquiterpene lactone parthenolide inhibits Wnt/-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2018,293(14):5335-5344.
APA Zhu, Xiaoliang.,Yuan, Chunmao.,Tian, Chenyang.,Li, Chen.,Nie, Fen.,...&Li, Lin.(2018).The plant sesquiterpene lactone parthenolide inhibits Wnt/-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1.JOURNAL OF BIOLOGICAL CHEMISTRY,293(14),5335-5344.
MLA Zhu, Xiaoliang,et al."The plant sesquiterpene lactone parthenolide inhibits Wnt/-catenin signaling by blocking synthesis of the transcriptional regulators TCF4/LEF1".JOURNAL OF BIOLOGICAL CHEMISTRY 293.14(2018):5335-5344.
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