Targeting the
ST3
beta‐galactoside alpha‐2,3‐sialyltransferase 1 (
ST3Gal1
) as a potential therapeutic strategy to overcome anti‐
VEGF
resistance in endometrial cancer
Abstract
Objective
To investigate the role of ST3 beta‐galactoside alpha‐2,3‐sialyltransferase 1 (ST3Gal1) in endometrial cancer (EC) progression and its potential as a therapeutic target to enhance the efficacy of antiangiogenic treatment.
Methods
ST3Gal1 expression and its clinical relevance were analyzed in EC tissues. Functional assays evaluated its effects on vascular endothelial growth factor‐A (VEGF‐A) expression, epithelial–mesenchymal transition (EMT), and cell invasiveness. Mechanistic studies, including Duolink proximity ligation assays and co‐immunoprecipitation, examined ST3Gal1–VEGF‐A interactions. ST3Gal1 was inhibited genetically or pharmacologically using soyasaponin I (SsaI), both in vitro and in xenograft models, alone or combined with bevacizumab. Angiogenic and EMT marker expression and focal adhesion kinase (FAK)/paxillin pathway activation were assessed.
Results
ST3Gal1 was amplified and overexpressed in EC and correlated with advanced stage, deep myometrial invasion, and poor prognosis. It directly glycosylated VEGF‐A and activated FAK/paxillin signaling, promoting VEGF‐A expression and EMT. ST3Gal1 inhibition via SsaI reduced VEGF‐A signaling, reversed EMT marker expression, and suppressed cell migration and invasion, particularly in RL95‐2 cells. In vivo, SsaI significantly inhibited tumor growth and angiogenesis, with the most pronounced effect observed in combination with bevacizumab. Dual treatment disrupted ST3Gal1–VEGF‐A interactions and downregulated angiogenic and EMT markers.
Conclusion
ST3Gal1 promotes EC progression by enhancing VEGF‐A signaling and EMT via the FAK/paxillin pathway. Its inhibition improves the efficacy of antiangiogenic therapy, supporting ST3Gal1 as a promising therapeutic target to overcome anti‐VEGF‐A resistance in advanced EC.
