Increased PrLZ-mediated androgen receptor transactivation promotes prostate cancer growth at castration-resistant stage
Increased PrLZ-mediated androgen receptor transactivation promotes prostate cancer growth at castration-resistant stage
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PrLZ介导的雄激素受体反式激活增加促进去势抵抗阶段前列腺癌的生长
DOI：
10.1093/carcin/bgs337
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发表时间：
2013-02-01
期刊：
影响因子：
4.7
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
--
作者：
Li, Lei;Xie, Hongjun;Chang, Chawnshang
大多数晚期前列腺癌（PCa）在雄激素剥夺治疗后会发展到去势抵抗期，但其分子机制仍不清楚。在本研究中，我们发现PrLZ，一个新发现的前列腺亮氨酸拉链基因，在前列腺癌中高表达，可以直接与雄激素受体（AR）相互作用，导致在去势抵抗条件下增强AR的反式激活。PrLZ可能通过改变AR构象，促进AR核转位，通过调节蛋白酶体途径抑制AR降解，从而增加前列腺特异性抗原表达，促进去势抵抗期PCa的生长。来自同一患者配对标本的临床PCa样本调查发现经典雄激素剥夺治疗后去势抵抗性PCa中PrLZ表达增加。通过ASC-J 9（R）或PrLZ-siRNA靶向AR-PrLZ复合物导致在各种人PCa细胞和体内小鼠PCa模型中PCa生长的抑制。总之，这些数据不仅加强了PrLZ在去势抵抗期从雄激素依赖性向雄激素非依赖性转变中的作用，而且它们还可能提供一种新的潜在疗法来对抗去势抵抗期的PCa。
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 (R) 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.