Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer.
Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer.
复制标题
AKR1C3激活的抑制克服了晚期前列腺癌对阿比罗酮的抗性。
DOI：
10.1158/1535-7163.mct-16-0186
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发表时间：
2017-01
影响因子：
5.7
通讯作者：
Gao AC
中科院分区：
文献类型：
--
作者：
Liu C;Armstrong CM;Lou W;Lombard A;Evans CP;Gao AC
阿比特龙通过抑制CYP17A1抑制胞内雄激素合成。然而，临床证据表明，雄激素合成不完全被阿比特龙抑制，持续的雄激素产生可能导致疾病复发。在本研究中，我们确定了AKR1C3，类固醇生成途径中的一种重要酶，作为通过增加内分泌雄激素合成和增强雄激素信号传导来驱动阿比特龙耐药性的关键机制。我们发现AKR1C3的过表达赋予对阿比特龙的抗性，而AKR1C3的下调使抗性细胞对阿比特龙治疗重新敏感。在阿比特龙抗性前列腺癌细胞中，AKR1C3过表达，并且胞内分泌雄激素的水平升高。此外，AKR1C3激活增加内分泌雄激素合成，并通过激活雄激素受体（AR）转录活性增强AR信号传导。用吲哚美辛（一种AKR1C3抑制剂）处理阿比特龙抗性细胞，通过降低胞内分泌雄激素的水平和减弱AR转录活性，克服了抗性并增强了体外和体内阿比特龙治疗。这些结果表明，AKR1C3激活是通过增加分泌内雄激素合成和增强雄激素信号传导而对阿比特龙耐药的关键机制。此外，该研究为研究使用吲哚美辛靶向AKR1C3与阿比特龙联合治疗晚期前列腺癌的临床试验提供了临床前原理验证。
Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 re-sensitizes resistant cells to abiraterone treatment. In abiraterone resistant prostate cancer cells, AKR1C3 is overexpressed and the levels of intracrine androgens are elevated. In addition, AKR1C3 activation increases intracrine androgen synthesis and enhances androgen receptor (AR) signaling via activating AR transcriptional activity. Treatment of abiraterone resistant cells with indomethacin, an AKR1C3 inhibitor, overcomes resistance and enhances abiraterone therapy both in vitro and in vivo by reducing the levels of intracrine androgens and diminishing AR transcriptional activity. These results demonstrate that AKR1C3 activation is a critical mechanism of resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. Furthermore, this study provides a preclinical proof-of-principle for clinical trials investigating the combination of targeting AKR1C3 using indomethacin with abiraterone for advanced prostate cancer.