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

Yujie Huang, Jiansong Fang, Weiqiang Lu, Zihao Wang, Qi Wang, Yuan Hou, Xingwu Jiang, Ofer Reizes, Justin Lathia, Ruth Nussinov, Charis Eng, Feixiong Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1143-1158.e6
JournalCell Chemical Biology
Volume26
Issue number8
DOIs
StatePublished - 15 Aug 2019

Keywords

  • Smoothened
  • angiogenesis
  • hedgehog signaling
  • systems pharmacology
  • triple-negative breast cancer
  • wogonoside

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