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Article

Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling

by
Xi Chen
1,
Xiaocheng Lv
1,
Lijie Gao
1,
Jiawei Liu
1,
Wei Wang
1,
Lichao Guo
1,
Mykhaylo S. Frasinyuk
2,
Wen Zhang
3,4,
David S. Watt
3,4,
Chunming Liu
3,4,* and
Xifu Liu
1,*
1
Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Anti-Tumor Molecular Target Technology Innovation Center, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China
2
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, 02094 Kyiv, Ukraine
3
Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
4
Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
*
Authors to whom correspondence should be addressed.
Cells 2023, 12(7), 1066; https://doi.org/10.3390/cells12071066
Submission received: 15 February 2023 / Revised: 16 March 2023 / Accepted: 28 March 2023 / Published: 31 March 2023
(This article belongs to the Special Issue From Mechanisms to Therapeutics: Wnt Signaling in Cancer)
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Abstract

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.
Keywords: chalcone derivative; colorectal cancer; Wnt/β-catenin signaling; TOP2A; cell cycle; cell proliferation chalcone derivative; colorectal cancer; Wnt/β-catenin signaling; TOP2A; cell cycle; cell proliferation

Share and Cite

MDPI and ACS Style

Chen, X.; Lv, X.; Gao, L.; Liu, J.; Wang, W.; Guo, L.; Frasinyuk, M.S.; Zhang, W.; Watt, D.S.; Liu, C.; et al. Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling. Cells 2023, 12, 1066. https://doi.org/10.3390/cells12071066

AMA Style

Chen X, Lv X, Gao L, Liu J, Wang W, Guo L, Frasinyuk MS, Zhang W, Watt DS, Liu C, et al. Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling. Cells. 2023; 12(7):1066. https://doi.org/10.3390/cells12071066

Chicago/Turabian Style

Chen, Xi, Xiaocheng Lv, Lijie Gao, Jiawei Liu, Wei Wang, Lichao Guo, Mykhaylo S. Frasinyuk, Wen Zhang, David S. Watt, Chunming Liu, and et al. 2023. "Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling" Cells 12, no. 7: 1066. https://doi.org/10.3390/cells12071066

APA Style

Chen, X., Lv, X., Gao, L., Liu, J., Wang, W., Guo, L., Frasinyuk, M. S., Zhang, W., Watt, D. S., Liu, C., & Liu, X. (2023). Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling. Cells, 12(7), 1066. https://doi.org/10.3390/cells12071066

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