A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling

Huang, Yujie1; Fang, Jiansong1,2; Lu, Weiqiang3,4; Wang, Zihao5; Wang, Qi1; Hou, Yuan2; Jiang, Xingwu3,4; Reizes, Ofer6,7,8; Lathia, Justin6,7,8; Nussinov, Ruth9,10; Eng, Charis2,6,7,11,12; Cheng, Feixiong2,6,7

2019-08-15

10.1016/j.chembiol.2019.05.004

Cell Chemical Biology   影响因子和分区

2451-9448

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease that lacks clinically actionable genetic alterations that limit targeted therapies. Here we explore a systems pharmacology approach that integrates drug-target networks and large-scale genomic profiles of TNBC and identify wogonoside, one of the major active flavonoids, as a potent angiogenesis inhibitor. We validate that wogonoside attenuates cell migration, tube formation, and rat aorta microvessel outgrowth, and reduces formation of blood vessels in chicken chorioallantoic membrane and TNBC cell-induced Matrigel plugs. In addition, wogonoside inhibits growth and angiogenesis in TNBC cell xenograft models. This network-based approach predicts, and we empirically validate, wogonoside's antiangiogenic effects resulting from vascular endothelial growth factor secretion. Mechanistically, wogonoside inhibits Gli1 nuclear translocation and transcriptional activities associated with Hedgehog signaling, by promoting Smoothened degradation in a proteasome-dependent mechanism. This study offers a powerful, integrated, systems pharmacology-based strategy for oncological drug discovery and identifies wogonoside as a potential TNBC angiogenesis inhibitor.

SCI

英语

其他

Frederick National Laboratory for Cancer Research, NIH[HHSN261200800001E]

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:000481604100011

CELL PRESS

Web of Science

1.Guangzhou Univ Chinese Med, Inst Clin Pharmacol, Guangzhou 510006, Guangdong, Peoples R China
2.Cleveland Clin, Lerner Res Inst, Genom Med Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA
3.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China
4.East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China
5.Southern Univ Sci & Technol, Shenzhen 518055, Guangdong, Peoples R China
6.Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Mol Med, Cleveland, OH 44195 USA
7.Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA
8.Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH 44915 USA
9.NCI, Computat Struct Biol Sect, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA
10.Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel
11.Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44195 USA
12.Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA

Huang, Yujie,Fang, Jiansong,Lu, Weiqiang,et al. A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling[J]. Cell Chemical Biology,2019,26(8):1143-+.

Huang, Yujie.,Fang, Jiansong.,Lu, Weiqiang.,Wang, Zihao.,Wang, Qi.,...&Cheng, Feixiong.(2019).A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling.Cell Chemical Biology,26(8),1143-+.

Huang, Yujie,et al."A Systems Pharmacology Approach Uncovers Wogonoside as an Angiogenesis Inhibitor of Triple-Negative Breast Cancer by Targeting Hedgehog Signaling".Cell Chemical Biology 26.8(2019):1143-+.