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

Xi Chen; Xiaocheng Lv; Lijie Gao; Jiawei Liu; Wei Wang; Lichao Guo; Mykhaylo S. Frasinyuk; Wen Zhang; David Watt; Chunming Liu; Xifu Liu

doi:10.3390/cells12071066

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

Xi Chen, Xiaocheng Lv, Lijie Gao, Jiawei Liu, Wei Wang, Lichao Guo, Mykhaylo S. Frasinyuk, Wen Zhang, David Watt, Chunming Liu, Xifu Liu

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Article number	1066
Journal	Cells
Volume	12
Issue number	7
DOIs	https://doi.org/10.3390/cells12071066
State	Published - Apr 2023

Bibliographical note

Funding 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).

Funding Information:
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.

Publisher Copyright:
© 2023 by the authors.

Keywords

TOP2A
Wnt/β-catenin signaling
cell cycle
cell proliferation
chalcone derivative
colorectal cancer

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cells12071066

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

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 = "TOP2A, Wnt/β-catenin signaling, cell cycle, cell proliferation, chalcone derivative, colorectal cancer",

author = "Xi Chen and Xiaocheng Lv and Lijie Gao and Jiawei Liu and Wei Wang and Lichao Guo and Frasinyuk, {Mykhaylo S.} and Wen Zhang and David Watt and Chunming Liu and Xifu Liu",

note = "Funding 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). Funding Information: 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. Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = apr,

doi = "10.3390/cells12071066",

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T1 - Chalcone Derivative CX258 Suppresses Colorectal Cancer via Inhibiting the TOP2A/Wnt/β-Catenin Signaling

AU - Chen, Xi

AU - Lv, Xiaocheng

AU - Gao, Lijie

AU - Liu, Jiawei

AU - Wang, Wei

AU - Guo, Lichao

AU - Frasinyuk, Mykhaylo S.

AU - Zhang, Wen

AU - Watt, David

AU - Liu, Chunming

AU - Liu, Xifu

N1 - Funding 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). Funding Information: 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. Publisher Copyright: © 2023 by the authors.

PY - 2023/4

Y1 - 2023/4

N2 - 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.

AB - 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.

KW - TOP2A

KW - Wnt/β-catenin signaling

KW - cell cycle

KW - cell proliferation

KW - chalcone derivative

KW - colorectal cancer

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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