Jia Wenqiao, Yu Zeyuan, Sun Feifei, Liu Ping, Han Bo
Department of Health Management Center, Qilu Hospital of Shandong University, Jinan, China.
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Immunol. 2025 Jul 17;16:1616046. doi: 10.3389/fimmu.2025.1616046. eCollection 2025.
The development of prostate cancer (PCa) remains a major health threat for men worldwide. Calcium/Calmodulin signaling pathway has been implicated to the initiation and progression of diverse human cancers. Loss or downregulation of Purkinje cell protein 4 (PCP4), is frequently observed in some prostate cancer patients, particularly those with castration-resistant prostate cancer (CRPC).
Public datasets were used to analyze PCP4 expression and the relationship between PCP4 expression and clinicopathological characteristics of PCa patients. Gain- and loss-of-function studies in PCa cell lines and mouse models were performed to characterize the role of PCP4 in tumor progression. A series of molecular and biochemical experiments were carried out in PCa cell lines to investigate the mechanism underlying PCP4-mediated tumor suppression.
(1) gene loss occurs at high frequency in PCa patients, and decreased expression of PCP4 correlates with poor prognosis of PCa, particularly CRPC development; (2) fusion frequently co-occurs with 4 deletion; (3) PCP4 suppresses prostate cancer progression and ; (4) PCP4 is an androgen receptor (AR) suppressed gene; (5) PCP4 was involved in the stabilization of CAMKK2 protein; (6) PCP4 inhibits PCa progression by regulating Ca/CAMKK2/AMPK/AR signaling axis.
Our findings elucidate the molecular mechanism that PCP4 downregulation promotes PCa progression via Ca/CAMKK2/AMPK/AR pathway, highlighting its significance in CRPC development.
前列腺癌（PCa）的发展仍然是全球男性面临的主要健康威胁。钙/钙调蛋白信号通路与多种人类癌症的发生和发展有关。在一些前列腺癌患者中，尤其是去势抵抗性前列腺癌（CRPC）患者中，经常观察到浦肯野细胞蛋白4（PCP4）的缺失或下调。
使用公共数据集分析PCP4的表达以及PCP4表达与PCa患者临床病理特征之间的关系。在PCa细胞系和小鼠模型中进行功能获得和功能丧失研究，以表征PCP4在肿瘤进展中的作用。在PCa细胞系中进行了一系列分子和生化实验，以研究PCP4介导的肿瘤抑制的潜在机制。
（1）PCa患者中基因缺失的发生率很高，PCP4表达降低与PCa的不良预后相关，尤其是CRPC的发展；（2）融合经常与4号缺失同时发生；（3）PCP4抑制前列腺癌进展；（4）PCP4是雄激素受体（AR）抑制的基因；（5）PCP4参与了CAMKK2蛋白的稳定；（6）PCP4通过调节Ca/CAMKK2/AMPK/AR信号轴抑制PCa进展。
我们的研究结果阐明了PCP4下调通过Ca/CAMKK2/AMPK/AR途径促进PCa进展的分子机制，突出了其在CRPC发展中的重要性。
