Most patients with advanced prostate cancer (PCa) initially respond well to androgen deprivation therapy (ADT) with antiandrogens, but most of them eventually become resistant to ADT. Here, we found that the antiandrogen Enzalutamide-resistant (EnzR) PCa cells can be suppressed by hyper-physiological doses of the androgen DHT. Mechanism dissection indicates that while androgens/androgen receptor (AR) can decrease BCL-2 expression to induce cell death, yet they can also simultaneously increase anti-apoptosis BCL-XL protein expression via decreasing its potential E3 ubiquitin ligase, PARK2, through transcriptionally increasing the miR-493-3p expression to target PARK2. Thus, targeting the high dose DHT/AR/miR-493-3p/PARK2/BCL-XL signaling with BCL-XL-shRNA can increase high-dose-DHT effect to better suppress EnzR cell growth via increasing the autophagic cell death. A preclinical study using in vivo mouse model also validated that suppressing BCL-XL led to enhance high dose DHT effect to induce PCa cell death. The success of human clinical trials in the future may help us to develop a novel therapy using high dose androgens to better suppress CRPC progression.

大多数晚期前列腺癌 (PCa) 患者最初对使用抗雄激素的雄激素剥夺疗法 (ADT) 反应良好，但大多数患者最终对 ADT 产生抗药性。在这里，我们发现抗雄激素 Enzalutamide (EnzR) PCa 细胞可以被高生理剂量的雄激素 DHT 抑制。机构解剖表明，尽管雄激素/雄激素受体（AR）可降低Bcl-2表达以诱导细胞死亡，但它们也可以同时提高抗凋亡BCL-XL的蛋白质表达通过通过转录增加 miR-493-3p 表达以靶向 PARK2，从而降低其潜在的 E3 泛素连接酶 PARK2。因此，用 BCL-XL-shRNA 靶向高剂量 DHT/AR/miR-493-3p/PARK2/BCL-XL 信号可以增加高剂量 DHT 效应，通过增加自噬细胞死亡更好地抑制 EnzR 细胞生长。一项使用体内小鼠模型的临床前研究也验证了抑制 BCL-XL 导致增强高剂量 DHT 效应以诱导 PCa 细胞死亡。未来人体临床试验的成功可能有助于我们开发一种使用高剂量雄激素更好地抑制 CRPC 进展的新疗法。