Targeting the NRF-2/RHOA/ROCK signaling pathway with a novel aziridonin, YD0514, to suppress breast cancer progression and lung metastasis

Dengfeng Li, Hong Wang, Ye Ding, Ziwei Zhang, Zhi Zheng, Jiabin Dong, Hyejin Kim, Xiaojing Meng, Qianjun Zhou, Jia Zhou, Lin Fang, Qiang Shen

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Metastasis is a major cause of breast cancer-associated mortality. Natural products extracted from herbs provide rich bioactive compounds with anticancer efficacy but may have limited or moderate potency and considerable toxicity. We developed a novel aziridonin, YD0514, by aziridinating oridonin, a natural product of the medicinal herb Rabdosia rubescens. In this study, we found that YD0514 significantly inhibited proliferation, motility, and adhesion of metastatic breast cancer cell lines MDA-MB-231, GI101, GILM2, and GILM3. YD0514 also decreased the protein expression of matrix metalloproteinases 2 and 9 (MMP2 and MMP9), focal adhesion kinase (FAK), and integrin family members. Importantly, YD0514 suppressed the growth of metastatic breast cancer xenograft tumors and significantly inhibited lung metastasis in vivo. Lastly, we showed that YD0514's anti-metastatic effect on highly aggressive breast cancer is mediated via regulating the NRF-2/RHOA/ROCK signaling pathway. These results demonstrate that YD0514, the first active analog based on an oridonin D-ring modification, has the potential to be developed as an anti-metastasis therapy for patients with metastatic cancers.

Original languageEnglish (US)
Pages (from-to)97-108
Number of pages12
JournalCancer Letters
Volume424
DOIs
StatePublished - Jun 28 2018

Keywords

  • Aziridonin
  • Breast cancer
  • Metastasis
  • NRF-2/RHOA/ROCK pathway
  • Oridonin
  • YD0514

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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