Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
Carcinogenesis. 2013 Feb;34(2):257-67. doi: 10.1093/carcin/bgs337. Epub 2012 Oct 26.
Most advanced prostate cancers (PCa) will develop into the castration-resistant stage following androgen deprivation therapy, yet the molecular mechanisms remain unclear. In this study, we found PrLZ, a newly identified Prostate Leucine Zipper gene that is highly expressed in PCa could interact with the androgen receptor (AR) directly leading to enhance AR transactivation in the castration-resistant condition. PrLZ might enhance AR transactivation via a change of AR conformation that leads to promotion of AR nuclear translocation and suppression of AR degradation via modulating the proteasome pathway, which resulted in increased prostate-specific antigen expression and promoted PCa growth at the castration-resistant stage. Clinical PCa sample survey from same-patient paired specimens found increased PrLZ expression in castration-resistant PCa following the classical androgen deprivation therapy. Targeting the AR-PrLZ complex via ASC-J9® or PrLZ-siRNA resulted in suppression of PCa growth in various human PCa cells and in vivo mouse PCa models. Together, these data not only strengthen PrLZ roles in the transition from androgen dependence to androgen independence during the castration-resistant stage, but they may also provide a new potential therapy to battle PCa at the castration-resistant stage.
大多数晚期前列腺癌（PCa）在接受雄激素剥夺治疗后会发展为去势抵抗阶段，但分子机制仍不清楚。在这项研究中，我们发现了 PrLZ，这是一个新鉴定的前列腺亮氨酸拉链基因，在 PCa 中高度表达，可直接与雄激素受体（AR）相互作用，导致去势抵抗状态下 AR 转录激活增强。PLZ 可能通过改变 AR 构象增强 AR 转录激活，导致 AR 核易位促进和 AR 降解抑制，通过调节蛋白酶体途径，导致前列腺特异性抗原表达增加，并促进去势抵抗阶段的 PCa 生长。对同一患者配对标本的临床 PCa 样本调查发现，在经典去势治疗后，去势抵抗性 PCa 中 PrLZ 的表达增加。通过 ASC-J9®或 PrLZ-siRNA 靶向 AR-PrLZ 复合物，可抑制各种人 PCa 细胞和体内小鼠 PCa 模型中的 PCa 生长。总之，这些数据不仅加强了 PrLZ 在去势抵抗阶段从雄激素依赖到雄激素非依赖的转变中的作用，而且可能为去势抵抗阶段的 PCa 提供一种新的潜在治疗方法。
