DCZ0415, a small‐molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/β‐catenin pathway in colorectal cancer
STAT3 Transcription Factor
0301 basic medicine
Epithelial-Mesenchymal Transition
TRIP13
colorectal cancer
Cell Cycle Proteins
Mice
03 medical and health sciences
Cell Line, Tumor
granzyme B
metastasis
Animals
Humans
Receptor, Fibroblast Growth Factor, Type 4
Wnt Signaling Pathway
RC254-282
Research Articles
beta Catenin
Cell Proliferation
DCZ0415
NF-kappa B
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Gene Expression Regulation, Neoplastic
FGFR4
ATPases Associated with Diverse Cellular Activities
Colorectal Neoplasms
DOI:
10.1002/1878-0261.13201
Publication Date:
2022-02-23T08:54:52Z
AUTHORS (12)
ABSTRACT
Thyroid receptor‐interacting protein 13 (TRIP13), a of the AAA‐ATPase family, is upregulated in various human cancers, including colorectal cancer (CRC). This study focused on inhibition TRIP13‐induced CRC progression and signalling by DCZ0415, small molecule targeting TRIP13. It demonstrated potent antitumour activity TRIP13‐deregulated cell lines, regardless their p53, KRAS, BRAF, epidermal growth factor receptor or microsatellite instability status. The treatment cells with DCZ0415 resulted decreased proliferation, induced cycle arrest G2‐M phase increased apoptosis. diminished xenograft tumour metastasis immunocompromised mice. reduced expression fibroblast 4 (FGFR4), signal transducer activator transcription 3 (STAT3), proteins associated epithelial‐mesenchymal transition nuclear kappa B (NF‐κB) pathways xenografts exhibiting high Additionally, cyclin D1, β‐catenin T‐cell 1, leading to inactivation Wnt/β‐catenin pathway. In syngeneic model, an immune response decreasing PD1 CTLA4 levels increasing granzyme B, perforin interferon gamma. sum, DCZ04145 inhibits TRIP13–FGFR4–STAT3 axis, inactivates NF‐κB signalling, activates reduces CRC. provides rationale evaluate clinically for subset CRCs that exhibit dysregulated TRIP13 FGFR4.
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