Prx1 enhances androgen receptor function in prostate cancer cells by increasing receptor affinity to dihydrotestosterone.
Prx1 enhances androgen receptor function in prostate cancer cells by increasing receptor affinity to dihydrotestosterone.
复制标题
DOI：
10.1158/1541-7786.mcr-08-0546
复制
发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Ip C
中科院分区：
文献类型：
--
作者：
Chhipa RR;Lee KS;Onate S;Wu Y;Ip C
雄激素受体(AR)信号在前列腺癌的发生发展中起着重要作用。过氧化还蛋白-1(peroxiredosin-1，PRX1)是一个新的过氧化物酶家族成员，它与AR发生物理作用，增强AR的反式激活作用。在本研究中，我们评价了PRX1在调节双氢睾酮(DHT)刺激的前列腺癌细胞生长和AR靶基因表达中的生物学意义。我们还研究了PRX1可能增强AR信号的机制。PRX1的贡献主要是通过稳定的PRX1基因敲除的方法进行评估。主要观察结果如下。(I)低水平的PRX1使细胞对生长刺激和DHT诱导的AR靶基因不敏感，因此当PRX1被抑制时，暴露于较高水平的DHT才能达到相同程度的反应。(2)PRX1可增加AR对DHT的亲和力，降低DHT从受体上解离的速率。(3)PRX1增强AR的N-端和C-端相互作用。更强的N-C相互作用与更强大的AR激活信号相一致，因为它使DHT紧凑在配体结合口袋中。(4)无论是野生型AR还是突变型AR，PRX1对AR配体结合亲和力和AR N-C相互作用的刺激作用都表现出来。上述发现使我们相信PRX1可能是阻止前列腺癌从雄激素依赖表型向雄激素耐药表型转变的治疗靶点。
Androgen receptor (AR) signaling plays a critical role in the development and progression of prostate cancer. It has been reported previously that peroxiredoxin-1 (Prx1), a member of a novel family of peroxidases, interacts physically with AR to enhance AR transactivation of target genes. In the present study, we evaluated the biological significance of Prx1 in modulating dihydrotestosterone (DHT)-stimulated growth and AR target gene expression of prostate cancer cells. We also investigated the mechanism by which Prx1 might potentiate AR signaling. The contribution of Prx1 was assessed mainly by using the approach of stable Prx1 knockdown. The major observations are as follows. (i) A low level of Prx1 desensitizes cells to growth stimulation and AR target gene induction by DHT, such that exposure to a higher level of DHT is required to reach the same magnitude of response when Prx1 is depressed. (ii) Prx1 increases the affinity of AR to DHT and decreases the rate of DHT dissociation from the occupied receptor. (iii) Prx1 enhances the N-terminus and C-terminus interaction of AR. A stronger N-C interaction is consistent with a more robust AR activation signal by keeping DHT tight in the ligand binding pocket. (iv) The stimulatory effects of Prx1 on AR ligand binding affinity and AR N-C interaction are manifested regardless of a wild-type or mutant AR. The above findings lead us to believe that Prx1 may be a therapeutic target in blocking the transition of prostate cancer from an androgen-dependent to an androgen-refractory phenotype.