The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a family of novel chalcone derivatives (CXs) that inhibited Wnt signaling and CRC cell proliferation. Among them, we selected CX258 for further in vitro and in vivo study to investigate the molecular mechanisms. We found that CX258 significantly inhibited β-catenin expression and nuclear translocation, inducing cell cycle arrest at the G2/M phase in CRC cells. Additionally, CX258 reduced the expression of DNA Topoisomerase II alpha (TOP2A) in CRC cells. Moreover, knocking down TOP2A by siRNAs inhibited the Wnt/β-catenin signaling pathway, a finding suggesting that CX258 inhibited Wnt/β-catenin signaling and CRC cell proliferation at least partially by modulating TOP2A. Further studies showed that CDK1 that interacts with TOP2A was significantly reduced after TOP2A knockdown. We demonstrated that CX258 significantly inhibited DLD-1 CRC cell xenografts in SCID mice. In summary, we identified CX258 as a promising candidate for colorectal cancer treatment by targeting the TOP2A/Wnt/β-catenin signaling pathway.
|State||Published - Apr 2023|
Bibliographical noteFunding Information:
Xifu Liu was supported by a Hebei Normal University Grant for High-level Talents (20180101) and a Health product development and transformation grant (202003) from Jianyuan Science & Technology (Zhangjiakou) Co., Ltd. for collaboration with Hebei Normal University. This work was also supported by the Key Research and Development Program of Hebei Province (20277720D).
We thank Lisi Li for her contribution to the screening of chalcone derivatives, Yang Liu for assistance in the identification of the compounds. We also thank Jianyuan Science & Technology (Zhangjiakou) Co., Ltd. for the financial support.
© 2023 by the authors.
- Wnt/β-catenin signaling
- cell cycle
- cell proliferation
- chalcone derivative
- colorectal cancer
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology (all)