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. Methods: 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. Results: 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. Conclusion: 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）仍然是一种高发且致命的疾病，尤其在晚期阶段。尽管有多种治疗方法，但对恩杂鲁胺等药物的耐药性仍是重大挑战。本研究旨在探讨半乳糖凝集素-1（Gal-1）在恩杂鲁胺耐药性前列腺癌中的作用，并评估其作为克服耐药性治疗靶点的潜力。方法：研究通过特异性siRNA介导的Gal-1敲低技术，在恩杂鲁胺耐药性前列腺癌细胞中评估其对细胞增殖及恩杂鲁胺治疗反应的影响。采用原位小鼠模型研究Gal-1敲低的体内效应。使用LLS30对Gal-1进行药理学靶向干预，并在体外和体内评估其效果。通过RNA测序（RNA-seq）分析探究相关分子机制。结果：研究发现恩杂鲁胺耐药性前列腺癌细胞中Gal-1表达显著上调。Gal-1敲低可抑制细胞增殖，并使耐药细胞在原位小鼠模型中恢复对恩杂鲁胺的敏感性。雄激素受体全长及AR-V7水平升高是前列腺癌恩杂鲁胺耐药的关键机制。Gal-1敲低可抑制AR和AR-V7的表达及其转录活性。LLS30治疗显著抑制恩杂鲁胺耐药性前列腺癌细胞的生长，并与恩杂鲁胺联用产生协同效应。值得注意的是，该联合疗法在体内显著抑制恩杂鲁胺耐药性移植瘤的生长。RNA-seq分析显示，LLS30通过抑制相关靶基因调控AR和AR-V7信号通路。结论：这些发现表明Gal-1是克服前列腺癌恩杂鲁胺耐药性的潜在治疗靶点。使用LLS30靶向Gal-1/AR/AR-V7轴为增强恩杂鲁胺疗效、解决晚期前列腺癌耐药问题提供了新策略。
肿瘤(癌症)患者之家