TY - JOUR
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 S.
AU - Liu, Chunming
AU - Liu, Xifu
N1 - 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
UR - http://www.scopus.com/inward/record.url?scp=85152303525&partnerID=8YFLogxK
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U2 - 10.3390/cells12071066
DO - 10.3390/cells12071066
M3 - Article
C2 - 37048139
AN - SCOPUS:85152303525
VL - 12
JO - Cells
JF - Cells
IS - 7
M1 - 1066
ER -