Targeting Trop2 by Bruceine D suppresses breast cancer metastasis by blocking Trop2/β-catenin positive feedback loop

Targeting Trop2 by Bruceine D suppresses breast cancer metastasis by blocking Trop2/β-catenin positive feedback loop

[Display omitted] •Trop2 played a vital role in metastasis by Trop2/β-catenin positive feedback loop.•Bruceine D inhibited cancer cells proliferation and metastasis by targeting Trop2.•Bruceine D suppressed Trop2-driven ECM-remodeling and EMT to reduce lung metastatic colonization in vivo.•Bruceine...

Full description

Saved in:
Bibliographic Details
Published in:Journal of advanced research 2024-04, Vol.58, p.193-210
Main Authors: Tang, Wenjuan, Hu, Yu, Tu, Kaihui, Gong, Zhengyan, Zhu, Man, Yang, Tianfeng, Sarwar, Ammar, Dai, Bingling, Zhang, Dongdong, Zhan, Yingzhuan, Zhang, Yanmin
Format: Article
Language:eng
Subjects:
Animals
beta Catenin - genetics
beta Catenin - metabolism
Breast cancer
Breast Neoplasms - pathology
Cell Line, Tumor
Disease Models, Animal
Feedback
Female
Humans
Lung colonization
Metastasis
Original
Quassins
Signal Transduction
Trop2
β-catenin
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] •Trop2 played a vital role in metastasis by Trop2/β-catenin positive feedback loop.•Bruceine D inhibited cancer cells proliferation and metastasis by targeting Trop2.•Bruceine D suppressed Trop2-driven ECM-remodeling and EMT to reduce lung metastatic colonization in vivo.•Bruceine D blocked Trop2/β-catenin complex, inducing β-catenin degradation though ubiquitin. Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody–drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/β-catenin positive loop, in which the Trop2/β-catenin complex prevented β-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized β-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing β-catenin in Trop2/β-catenin positive loop,
ISSN:2090-1232
2090-1224