Department of Experimental Pathology and Tumor Biology and Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku 467-8601, Nagoya, Japan.
Department of Experimental Pathology and Tumor Biology and
Carcinogenesis. 2014 Sep;35(9):1962-7. doi: 10.1093/carcin/bgu048. Epub 2014 Feb 22.
There is a need for exploration of new therapeutic strategies that target distinct molecular mechanisms of castration-resistant prostate cancer (CRPC) because its emergence following androgen deprivation therapy is a major clinical problem. In this report, we investigated the role of glutathione peroxidase 2 (GPX2) in CRPC. GPX2 expression was analyzed in rat and human CRPC cells. Next, we determined the proliferation rate and level of reactive oxygen species (ROS) in GPX2-small interfering RNA (siRNA)-transfected CRPC cells. For in vivo analysis, siRNA-transfected cells were subcutaneously implanted into normal and castrated nude mice. Further, immunohistochemical and prognostic analyses of GPX2 were performed using human specimens. Silencing of GPX2 caused significant growth inhibition and increased intracellular ROS in both rat (PCai1) and human (PC3) CRPC cells. Flow cytometry and western blot analyses revealed that the decrease in proliferation rate of the GPX2-silenced cells was due to cyclin B1-dependent G2/M arrest. Furthermore, knockdown of Gpx2 inhibited tumor growth of PCai1 cells in castrated mice. Immunohistochemical analyses indicated that expression of GPX2 was significantly higher in residual cancer foci after neoadjuvant hormonal therapy than in hormone naive cancer foci. Moreover, patients with high GPX2 expression in biopsy specimen had significantly lower prostate-specific antigen recurrence-free survival and overall survival than those with no GPX2 expression. These findings suggest that GPX2 is a prognostic marker in CRPC and affects proliferation of prostate cancer under androgen depletion partially through protection against ROS signaling.
需要探索针对去势抵抗性前列腺癌 (CRPC) 不同分子机制的新治疗策略，因为其在雄激素剥夺治疗后出现是一个主要的临床问题。在本报告中，我们研究了谷胱甘肽过氧化物酶 2 (GPX2) 在 CRPC 中的作用。分析了大鼠和人 CRPC 细胞中 GPX2 的表达。接下来，我们测定了 GPX2 小干扰 RNA (siRNA) 转染的 CRPC 细胞的增殖率和活性氧 (ROS) 水平。为了进行体内分析，将 siRNA 转染的细胞皮下植入正常和去势裸鼠中。进一步，使用人标本进行了 GPX2 的免疫组织化学和预后分析。沉默 GPX2 导致大鼠 (PCai1) 和人 (PC3) CRPC 细胞的生长明显抑制和细胞内 ROS 增加。流式细胞术和 Western blot 分析显示，GPX2 沉默细胞增殖率的降低是由于 cyclin B1 依赖性 G2/M 期阻滞所致。此外，Gpx2 的敲低抑制了去势小鼠中 PCai1 细胞的肿瘤生长。免疫组织化学分析表明，在新辅助激素治疗后的残留癌灶中 GPX2 的表达明显高于激素初治癌灶。此外，活检标本中 GPX2 表达较高的患者前列腺特异性抗原无复发生存率和总生存率明显低于无 GPX2 表达的患者。这些发现表明，GPX2 是 CRPC 的预后标志物，并通过对 ROS 信号的保护部分影响雄激素耗竭下前列腺癌的增殖。
