Guo Yuqi, Zhang Zhiyuan, Dong Lintao, Shi Xinyi, Li Xiaohan, Luo Mingxiu, Fu Yajuan, Gao Yujing
Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
The First Clinical Medical School, Ningxia Medical University, Yinchuan, China.
J Transl Med. 2025 Mar 18;23(1):347. doi: 10.1186/s12967-025-06322-8.
Prostate cancer (PCa) is a leading cause of cancer-related mortality in men globally. While androgen deprivation therapy (ADT) can extend the asymptomatic phase and overall survival of patients with metastatic PCa, prolonged ADT often leads to the development of castration-resistant prostate cancer (CRPC) within 18-24 months. The mechanisms underlying CRPC remain incompletely understood, presenting a significant challenge in clinical prostate cancer treatment.
In this study, we investigated the role of Wnt5a, a member of the Wnt family, in CRPC. Tumor tissues from CRPC patients were analyzed to assess the expression levels of Wnt5a. Prostate cancer cells were used to examine the impact of Wnt5a on androgen-dependent and -independent growth, as well as sensitivity to bicalutamide. RNA-seq analysis, qRT-PCR, intracellular cholesterol content and the activation of the androgen receptor (AR) signaling pathway were evaluated to elucidate the mechanistic role of Wnt5a in CRPC progression. Drug target Mendelian randomization analysis was performed to investigate the effect of PCSK9 inhibitor on prostate cancer.
Our study revealed a significant overexpression of Wnt5a in tissues from CRPC tumors. Wnt5a was found to enhance both androgen-dependent and -independent growth in prostate cancer cells while reducing their sensitivity to bicalutamide. Mechanistically, Wnt5a was shown to upregulate intracellular free cholesterol content and activate the AR signaling pathway, contributing to hormone therapy resistance in CRPC. PCSK9 inhibitor significantly reduced the risk of PCa.
The findings of this study highlight a novel molecular mechanism underlying endocrine therapy resistance in CRPC mediated by Wnt5a. Targeting Wnt5a or reducing cholesterol level would be a promising therapeutic strategy for the treatment of CRPC, providing new insights into potential avenues for combating this challenging form of prostate cancer.
前列腺癌（PCa）是全球男性癌症相关死亡的主要原因。虽然雄激素剥夺疗法（ADT）可以延长转移性PCa患者的无症状期和总生存期，但长期ADT通常会在18 - 24个月内导致去势抵抗性前列腺癌（CRPC）的发生。CRPC的潜在机制仍未完全明确，这在临床前列腺癌治疗中构成了重大挑战。
在本研究中，我们调查了Wnt家族成员Wnt5a在CRPC中的作用。分析CRPC患者的肿瘤组织以评估Wnt5a的表达水平。使用前列腺癌细胞来检测Wnt5a对雄激素依赖性和非依赖性生长以及对比卡鲁胺敏感性的影响。评估RNA测序分析、定量逆转录聚合酶链反应、细胞内胆固醇含量和雄激素受体（AR）信号通路的激活，以阐明Wnt5a在CRPC进展中的机制作用。进行药物靶点孟德尔随机化分析以研究前蛋白转化酶枯草溶菌素9（PCSK9）抑制剂对前列腺癌的影响。
我们的研究显示CRPC肿瘤组织中Wnt5a显著过表达。发现Wnt5a可增强前列腺癌细胞的雄激素依赖性和非依赖性生长，同时降低其对比卡鲁胺的敏感性。从机制上讲，Wnt5a被证明可上调细胞内游离胆固醇含量并激活AR信号通路，导致CRPC中的激素治疗抵抗。PCSK9抑制剂显著降低了PCa的风险。
本研究结果突出了Wnt5a介导的CRPC内分泌治疗抵抗的一种新分子机制。靶向Wnt5a或降低胆固醇水平可能是治疗CRPC的一种有前景的治疗策略，为对抗这种具有挑战性的前列腺癌形式提供了新的潜在途径。
