Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer.
Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-13-1863
复制
发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Balk SP
中科院分区：
文献类型：
--
作者：
Yu Z;Chen S;Sowalsky AG;Voznesensky OS;Mostaghel EA;Nelson PS;Cai C;Balk SP
在去势（去势抵抗性前列腺癌，CRPC）和随后的阿比特龙（进一步抑制雄激素合成的CYP 17 A1抑制剂）治疗后进展的前列腺癌（PCa）中介导雄激素受体（AR）再活化的机制仍不清楚。检查PCa异种移植物以鉴定去势和阿比特龙后的进展机制。在阿比特龙耐药的VCaP异种移植物中，AR再活化与瘤内雄激素的恢复或AR协同调节因子的改变无关。相比之下，与去势前的异种移植物相比，编码全长AR（AR-FL）和组成型活性剪接变体（AR-V7）的mRNA增加，其中AR-V7相对于AR-FL增加。这种向AR-V7的转变是由于反馈机制，由此雄激素配体的AR刺激抑制AR-V7相对于AR-FL转录物的产生的蛋白质的表达。然而，尽管AR-V7 mRNA增加，但在耐药VCaP异种移植物和CRPC临床样品中，相对于AR-FL，它仍然是次要的转录物（<1%）。在去势抵抗性VCaP异种移植物和雄激素剥夺的VCaP细胞中，AR-V7蛋白表达相对于AR-FL类似地低，但是在这些后者细胞中的弱基础AR活性被AR-V7 siRNA进一步抑制。在这些低水平下的AR-V7不足以恢复AR活性，但其在雄激素剥夺后的快速诱导允许肿瘤保留存活可能需要的基础AR活性，直到出现更有效的机制来激活AR。当与靶向AR配体结合结构域的疗法联合使用时，靶向AR剪接变体的药剂可能最有效。
Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer (PCa) that progresses after castration (castration-resistant prostate cancer, CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear. PCa xenografts were examined to identify mechanism of progression after castration and abiraterone. AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR co-regulators. In contrast, mRNA encoding full length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared to xenografts prior to castration, with an increase in AR-V7 relative to AR-FL. This shift towards AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. However, despite the increases in AR-V7 mRNA, it remained a minor transcript (<1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA. AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR. Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand binding domain.