Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer
Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer
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DOI：
10.1002/pros.22504
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发表时间：
2012-10-01
期刊：
影响因子：
2.8
通讯作者：
Denmeade, Samuel R.
中科院分区：
文献类型：
--
作者：
Isaacs, John T.;D'Antonio, Jason M.;Denmeade, Samuel R.
临床材料的细胞培养物/异种移植物和基因阵列证明，去势抗性前列腺癌（CRPC）细胞的发展涉及获得适应性自动调节，导致在低雄激素环境中雄激素受体（AR）蛋白表达增加>25倍。然而，当超生理性雄激素被急性替代时，这种自适应AR增加在去势宿主中是一种不利因素。细胞同步化/抗雄激素反应是由于AR在G1早期与复制位点起点（ORS）处的复制复合物（RC）结合，与S期单轮复制的DNA许可/限制有关。当CRPC细胞急性暴露于超生理雄激素时，适应性增加的核AR过度稳定，阻止有丝分裂中的充分降解，抑制DNA再许可，从而在随后的细胞周期中死亡。这些机制结果和AR/RC结合发生在直接来自患者的转移性CRPC中的事实为双极雄激素治疗（BAT）在慢性雄激素消融治疗进展的患者中提供了范式转变的依据。BAT涉及在急性超生理性雄激素阶段之间交替给予连续周期，然后进行急性消融，以利用CRPC细胞中AR与RC的适应性自动调节和结合产生的脆弱性。BAT疗法在异种移植物中有效，并且基于阳性结果已经进入临床测试。前列腺72：14911505，2012。(c)2012 Wiley Periodicals，Inc.
Cell culture/xenograft and gene arrays of clinical material document that development of castration resistant prostate cancer (CRPC) cells involves acquisition of adaptive auto-regulation resulting in >25-fold increase in Androgen Receptor (AR) protein expression in a low androgen environment. Such adaptive AR increase paradoxically is a liability in castrated hosts, however, when supraphysiologic androgen is acutely replaced. Cell synchronization/anti-androgen response is due to AR binding to replication complexes (RC) at origin of replication sites (ORS) in early G1 associated with licensing/restricting DNA for single round of duplication during S-phase. When CRPC cells are acutely exposed to supraphysiologic androgen, adaptively increased nuclear AR is over-stabilized, preventing sufficient degradation in mitosis, inhibiting DNA re-licensing, and thus death in the subsequent cell cycle. These mechanistic results and the fact that AR/RC binding occurs in metastatic CRPCs directly from patients provides a paradigm shifting rationale for bipolar androgen therapy (BAT) in patient progressing on chronic androgen ablation. BAT involves giving sequential cycles alternating between periods of acute supraphysiologic androgen followed by acute ablation to take advantage of vulnerability produced by adaptive auto-regulation and binding of AR to RC in CRPC cells. BAT therapy is effective in xenografts and based upon positive results has entered clinical testing. Prostate 72:14911505, 2012. (c) 2012 Wiley Periodicals, Inc.