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A Novel Imidazopyridine Derivative Exhibits Anticancer Activity in Breast Cancer by Inhibiting Wnt/β‑catenin Signaling

Authors
  • He, Liu-Jun1
  • Yang, Dong-Lin1
  • Chen, He-Ying1, 2, 2
  • Huang, Jiu-Hong1
  • Zhang, Ya-Jun1
  • Qin, Hong-Xia1
  • Wang, Juan-Li1
  • Tang, Dian-Yong1
  • Chen, Zhong-Zhu1
  • 1 Chongqing University of Arts and Sciences, Chongqing, 402160
  • 2 Chongqing Medical University, Chongqing, 400016
Type
Published Article
Journal
OncoTargets and Therapy
Publisher
Dove Medical Press
Publication Date
Oct 09, 2020
Volume
13
Pages
10111–10121
Identifiers
DOI: 10.2147/OTT.S266752
PMID: 33116593
PMCID: PMC7553630
Source
PubMed Central
Keywords
License
Green

Abstract

Background Breast cancer exhibits poor prognosis and high relapse rates following chemotherapy therapeutics. Thus, this study aims to develop effective novel agents regulating the core molecular pathway of breast cancer such as Wnt/β-catenin signaling. Methods The present study screened a novel inhibitor, called “C188”, using MTT assay. The molecular formula of C188 is C21H15FN4O3 and the molecular weight is 390. Flow cytometry and Western blotting were employed to assess cell cycle arrest after treatment with C188. Wound-healing and transwell assays were applied to measure the cell migration and invasion viability. The regulatory effects of C188 on Wnt/β‑catenin signaling and localization of β‑catenin in the nucleus were investigated by Western blotting and immunofluorescence. Results We found that C188 significantly suppressed proliferation and growth in a dose- and time-dependent manner in breast cancer cells, but not in normal breast cells. The inhibitory effect was caused by cell cycle arrest at the G1-phase which is induced by C188 treatment. Additionally, C188 dramatically inhibited cell migration of breast cancer cells in a dose-dependent manner. The migration inhibition was attributed to the suppression of Wnt/β‑catenin signaling and localization of β‑catenin in the nucleus mediated by regulating phosphorylation of β‑catenin and its subsequent stability. Furthermore, the target genes, including Axin 2 , c-JUN , and c-Myc , were downregulated due to the decrease of β‑catenin in the nucleus after exposure to C188. Conclusion C188 treatment resulted in the downregulation of cyclin D which led to cell cycle arrest at the G1 phase, and the inhibition of cell migration, indicating that C188 may be an effective novel therapeutic candidate as a potential treatment for human breast cancer.

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