Wang Hsiao-Chi, Gao Allen C, Xia Roger, Wu Chun-Te, Hsu Ssu-Wei, Chen Ching-Hsien, Shih Tsung-Chieh
Department of Research and Development, Kibio Inc., Houston, TX 77021, USA.
Department of Urologic Surgery, University of California at Davis, Davis, CA 95718, USA.
Cancers (Basel). 2025 Jan 22;17(3):351. doi: 10.3390/cancers17030351.
BACKGROUND/OBJECTIVE: 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 aimed to investigate the role of Galectin-1 (Gal-1) in enzalutamide-resistant PCa and assess its potential as a therapeutic target to overcome resistance.
The study utilized specific siRNA-mediated knockdown of Gal-1 in enzalutamide-resistant PCa cells to evaluate its effects on cell proliferation and response to enzalutamide treatment. An orthotopic mouse model was employed to examine the in vivo impact of Gal-1 knockdown. Pharmacological targeting of Gal-1 was conducted using LLS30, and its effects were assessed both in vitro and in vivo. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanisms underlying the observed effects.
The findings demonstrated significant upregulation of Gal-1 in enzalutamide-resistant PCa cells. Gal-1 knockdown inhibited cell proliferation and resensitized resistant cells to enzalutamide treatment in the orthotopic mouse model. Elevated levels of androgen receptor full-length and AR-V7 are key mechanisms under-lying resistance to enzalutamide in PCa. Gal-1 knockdown suppressed AR and AR-V7 expression and their transcriptional activity. Treatment with LLS30 significantly suppressed the growth of enzalutamide-resistant PCa cells and exhibited synergistic effects when combined with enzalutamide. Notably, this combination therapy significantly inhibited the growth of enzalutamide-resistant xenografts in vivo. RNA-seq analysis revealed that LLS30 modulates AR and AR-V7 signaling through the inhibition of associated target genes.
These findings highlight Gal-1 as a promising therapeutic target for overcoming enzalutamide resistance in PCa. Targeting the Gal-1/AR/AR-V7 axis with LLS30 presents a novel strategy to enhance enzalutamide efficacy and address drug resistance in advanced PCa.
背景/目的：前列腺癌（PCa）仍然是一种常见且致命的疾病，尤其是在晚期。尽管有多种可用的治疗方法，但对恩杂鲁胺等药物的耐药性仍然带来重大挑战。本研究旨在探讨半乳糖凝集素-1（Gal-1）在恩杂鲁胺耐药性PCa中的作用，并评估其作为克服耐药性的治疗靶点的潜力。
该研究利用特异性siRNA介导的方法敲低恩杂鲁胺耐药性PCa细胞中的Gal-1，以评估其对细胞增殖和对恩杂鲁胺治疗反应的影响。采用原位小鼠模型来研究Gal-1敲低的体内影响。使用LLS30对Gal-1进行药物靶向，并在体外和体内评估其效果。进行RNA测序（RNA-seq）分析以探索观察到的效果背后的分子机制。
研究结果表明，Gal-1在恩杂鲁胺耐药性PCa细胞中显著上调。在原位小鼠模型中，Gal-1敲低抑制了细胞增殖，并使耐药细胞对恩杂鲁胺治疗重新敏感。雄激素受体全长和AR-V7水平升高是PCa对恩杂鲁胺耐药的关键机制。Gal-1敲低抑制了AR和AR-V7的表达及其转录活性。LLS30治疗显著抑制了恩杂鲁胺耐药性PCa细胞的生长，并且与恩杂鲁胺联合使用时表现出协同作用。值得注意的是，这种联合疗法在体内显著抑制了恩杂鲁胺耐药性异种移植瘤的生长。RNA-seq分析表明，LLS30通过抑制相关靶基因来调节AR和AR-V7信号通路。
这些发现突出了Gal-1作为克服PCa中恩杂鲁胺耐药性的有前景的治疗靶点。用LLS30靶向Gal-1/AR/AR-V7轴提出了一种新策略，可增强恩杂鲁胺疗效并解决晚期PCa中的耐药性问题。
