A novel ß-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer.
Sci Adv
; 8(17): eabm3108, 2022 04 29.
Article
em En
| MEDLINE
| ID: mdl-35486727
ABSTRACT
Dysregulated Wnt/ß-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between ß-catenin and its coactivator BCL9. We identified a compound that consistently bound to ß-catenin and specifically inhibited in vivo native ß-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/ß-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Beta Catenina
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article