OncoTargets and Therapy (Oct 2020)
A Novel Imidazopyridine Derivative Exhibits Anticancer Activity in Breast Cancer by Inhibiting Wnt/β‑catenin Signaling
Abstract
Liu-Jun He,1 Dong-Lin Yang,1 He-Ying Chen,1– 3 Jiu-Hong Huang,1 Ya-Jun Zhang,1 Hong-Xia Qin,1 Juan-Li Wang,1 Dian-Yong Tang,1 Zhong-Zhu Chen1 1National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People’s Republic of China; 2Division of Molecular Nephrology and the Creative Training Center for Undergraduates, The Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, The College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People’s Republic of China; 3The Undergraduates Class of 2016 Entry the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, People’s Republic of ChinaCorrespondence: Dong-Lin Yang; Zhong-Zhu ChenNational & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Collaborative Innovation Center of Targeted and Innovative Therapeutics, College of Pharmacy & International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing 402160, People’s Republic of ChinaTel/Fax +86-23-61162836Email [email protected]; [email protected]: 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.Keywords: C188, breast cancer, proliferation, cell cycle, cell migration, Wnt/β-catenin
