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首页> 外文期刊>Molecular cancer therapeutics >Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer
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Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer

机译：AKR1C3活化的抑制克服了晚期前列腺癌中的抗止血剂

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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 resensitizes 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. (C) 2016 AACR.
机译：AbiraTerone通过CYP17A1的抑制抑制肠腺雄激素合成。然而，临床证据表明，Abiraatorone没有完全抑制雄激素合成，并且持续的雄激素产量可能导致疾病复发。在本研究中，我们鉴定了AKR1C3，这是甾体化途径中的重要酶，作为通过增加肠腺雄激素合成和增强雄激素信号传导抗ABIRATERO的关键机制。我们发现，AKR1C3的过度表达赋予ABIRATERONE的抗性，同时AKR1C3的下调将抗性细胞恢复到ABIRATERONE治疗中。在AbiraatorOne抗性前列腺癌细胞中，AKR1C3过表达，血管肾酮的水平升高。此外，AKR1C3激活增加了肠肾上腺素合成，并通过激活AR转录活性增强雄激素受体（AR）信号传导。用吲哚美辛，AKR1C3抑制剂的耐药细胞治疗耐药性，克服抗性，通过降低肠肾性水平和减少AR转录活性的体外和体内增强Abiraatorone治疗。这些结果表明，AKR1C3活化是通过增加肠内雄激素合成和增强雄激素信号来抵抗抵抗抵抗力的临界机制。此外，本研究为临床试验提供了临床原则原理，用于研究靶向AKR1C3使用吲哚美辛与Abiraaterone进行治疗前列腺癌的组合。 （c）2016 AACR。

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