Inhibition of Galectin-1 and androgen receptor axis enhances enzalutamide treatment in enzalutamide resistant prostate cancer

Prostate cancer (PCa) remains a prevalent and deadly disease, particularly in its advanced stages. Despite various available treatments, resistance to drugs like enzalutamide continues to present significant challenges. This study demonstrated the significant upregulation of Galectin-1 (Gal-1) in enzalutamide-resistant PCa cells. Specific siRNA-mediated knockdown of Gal-1 inhibited proliferation in enzalutamide-resistant prostate cancer cells and resensitized them to enzalutamide treatment in an orthotopic mouse model. Elevated levels of androgen receptor full length and AR-V7 are key mechanisms underlying resistance to enzalutamide in PCa. Our findings showed that Gal-1 knockdown suppressed AR and AR-V7 expression and their transcriptional activity. In addition, pharmacological targeting of Gal-1 using LLS30 significantly suppressed the growth of enzalutamide-resistant PCa cells and exhibited synergistic effects when combined with enzalutamide. Notably, this combination significantly inhibited the growth of enzalutamide-resistant xenografts in vivo. Furthermore, RNA-seq analysis further revealed that LLS30 modulates AR and AR-V7 signaling through the inhibition of associated target genes. These findings highlighted Gal-1 as a promising therapeutic target for combating enzalutamide resistance in PCa. Importantly, targeting the Gal-1/AR/AR-V7 axis with LLS30 emerges as a promising strategy to enhance the efficacy of enzalutamide treatment and address enzalutamide resistance in PCa.