Ning Peng, Zhong Jia-Guo, Jiang Fan, Zhang Yi, Zhao Jie, Tian Feng, Li Wei
Department of Histology and EmbryologyFourth Military Medical University, Xi'an, China Department of Tumor Radiotherapy3rd Hospital of PLA, Bao Ji, China.
Section 2 of Department of Surgery42nd Hospital of PLA, Jiajiang County Leshan City, Sichuan, China.
Endocr Relat Cancer. 2016 Aug;23(8):595-607. doi: 10.1530/ERC-16-0126. Epub 2016 Jun 24.
Understanding how castration-resistant prostate cancer (CRPC) cells survive the androgen-deprivation condition is crucial for treatment of this advanced prostate cancer (PCa). Here, we reported for the first time the up-regulation of protein S (PROS), an anticoagulant plasma glycoprotein with multiple biological functions, in androgen-insensitive PCa cells and in experimentally induced castration-resistant PCa cells. Overexpression of exogenous PROS in LNCaP cells reduced androgen deprivation-induced apoptosis and enhanced anchorage-dependent clonogenic ability under androgen deprivation condition. Reciprocally, PROS1 knockdown inhibited cell invasiveness and migration, caused the growth inhibition of castration-resistant tumor xenograft under androgen-depleted conditions, and potentiated Taxol (a widely prescribed anti-neoplastic agent)-mediated cell death in PC3 cells. Furthermore, PROS overexpression significantly stimulated AKT activation but failed to evoke oxidative stress in LNCaP cells under normal condition, suggesting that the malignance-promoting effects of the above-mentioned pathway may occur in the order of oxidative stress/PROS/AKT. The potential mechanism may be due to control of oxidative stress-elicited activation of PI3K-AKT-mTOR pathway. Taken together, our gain-of-function, loss-of-function analyses suggest that PROS may facilitate cell proliferation and promote castration resistance in human castration-resistant PCa-like cells via its apoptosis-regulating property. Future study emphasizing on delineating how PROS regulate cellular processes controlling transformation during the development of castration resistance should open new doors for the development of novel therapeutic targets for CRPC.
了解去势抵抗性前列腺癌（CRPC）细胞如何在雄激素剥夺条件下存活对于治疗这种晚期前列腺癌（PCa）至关重要。在此，我们首次报道了蛋白S（PROS）在雄激素不敏感的PCa细胞和实验诱导的去势抵抗性PCa细胞中的上调，PROS是一种具有多种生物学功能的抗凝血浆糖蛋白。在LNCaP细胞中外源性PROS的过表达减少了雄激素剥夺诱导的细胞凋亡，并增强了雄激素剥夺条件下的锚定依赖性克隆形成能力。相反，PROS1基因敲低抑制了细胞侵袭和迁移，导致去势抵抗性肿瘤异种移植在雄激素缺乏条件下生长受抑制，并增强了紫杉醇（一种广泛使用的抗肿瘤药物）介导的PC3细胞死亡。此外，PROS过表达在正常条件下显著刺激了LNCaP细胞中AKT的激活，但未能引发氧化应激，这表明上述途径的促恶性作用可能按氧化应激/PROS/AKT的顺序发生。潜在机制可能是由于对氧化应激引发的PI3K-AKT-mTOR途径激活的控制。综上所述，我们的功能获得和功能丧失分析表明，PROS可能通过其凋亡调节特性促进人去势抵抗性PCa样细胞的增殖并促进去势抵抗。未来着重于阐明PROS在去势抵抗发展过程中如何调节控制细胞转化的细胞过程的研究应为CRPC新型治疗靶点的开发打开新的大门。
