Yu Ziyang, Cai Changmeng, Gao Shuai, Simon Nicholas I, Shen Howard C, Balk Steven P
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
Clin Cancer Res. 2014 Aug 1;20(15):4075-85. doi: 10.1158/1078-0432.CCR-14-0292. Epub 2014 May 29.
Galeterone inhibits the enzyme CYP17A1 and is currently in phase II clinical trials for castration-resistant prostate cancer (CRPC). Galeterone is also a direct androgen receptor (AR) antagonist and may enhance AR degradation. This study was undertaken to determine the molecular basis for AR effects and their therapeutic potential.
Effects of galeterone on AR expression and activities were examined in prostate cancer cell lines.
Similar to the AR antagonist enzalutamide, but in contrast to bicalutamide, galeterone did not induce binding of a constitutively active VP16-AR fusion protein to reporter genes and did not induce AR recruitment to endogenous androgen-regulated genes based on chromatin immunoprecipitation. Galeterone at low micromolar concentrations that did not induce cellular stress responses enhanced AR protein degradation in LNCaP and C4-2 cells, which express a T878A mutant AR, but not in prostate cancer cells expressing wild-type AR. Further transfection studies using stable LNCaP and PC3 cell lines ectopically expressing wild-type or T878A-mutant ARs confirmed that galeterone selectively enhances degradation of the T878A-mutant AR.
Similar to enzalutamide, galeterone may be effective as a direct AR antagonist in CRPC. It may be particularly effective against prostate cancer cells with the T878A AR mutation but may also enhance degradation of wild-type AR in vivo through a combination of direct and indirect mechanisms. Finally, these findings show that conformational changes in AR can markedly enhance its degradation and thereby support efforts to develop further antagonists that enhance AR degradation.
加列酮可抑制细胞色素P450 17α-羟化酶（CYP17A1），目前正处于去势抵抗性前列腺癌（CRPC）的II期临床试验阶段。加列酮还是一种直接的雄激素受体（AR）拮抗剂，可能会增强AR的降解。本研究旨在确定AR效应的分子基础及其治疗潜力。
在前列腺癌细胞系中检测加列酮对AR表达和活性的影响。
与AR拮抗剂恩杂鲁胺相似，但与比卡鲁胺不同，加列酮不会诱导组成型活性VP16-AR融合蛋白与报告基因结合，也不会基于染色质免疫沉淀诱导AR募集至内源性雄激素调节基因。低微摩尔浓度的加列酮不会诱导细胞应激反应，但可增强LNCaP和C4-2细胞（表达T878A突变型AR）中的AR蛋白降解，而对表达野生型AR的前列腺癌细胞则无此作用。使用稳定转染野生型或T878A突变型AR的LNCaP和PC3细胞系进行的进一步转染研究证实，加列酮可选择性增强T878A突变型AR的降解。
与恩杂鲁胺相似，加列酮在CRPC中可能作为直接的AR拮抗剂有效。它可能对具有T878A AR突变的前列腺癌细胞特别有效，但也可能通过直接和间接机制的组合在体内增强野生型AR的降解。最后，这些发现表明AR的构象变化可显著增强其降解，从而支持开发进一步增强AR降解的拮抗剂的努力。
