Auranofin lethality to prostate cancer includes inhibition of proteasomal deubiquitinases and disrupted androgen receptor signaling
Auranofin lethality to prostate cancer includes inhibition of proteasomal deubiquitinases and disrupted androgen receptor signaling
复制标题
金诺芬对前列腺癌的致死作用包括抑制蛋白酶体去泛素酶和破坏雄激素受体信号传导
DOI：
10.1016/j.ejphar.2019.01.004
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发表时间：
2019-03-05
影响因子：
5
通讯作者：
Huang, Hongbiao
中科院分区：
文献类型：
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作者：
Liu, Ningning;Guo, Zhiqiang;Huang, Hongbiao
Auranofin （Aur）抑制硫氧还蛋白还原酶，也是19S蛋白酶体相关去泛素酶的抑制剂，靶向USP14和UCHL5。雄激素受体在前列腺癌（PCa）中经常过度表达，并与前列腺癌的生长和进展密切相关。因此，雄激素剥夺疗法（ADT）减少雄激素已应用于治疗雄激素受体介导的前列腺癌几十年。然而，大多数ADT治疗的患者由于去势抵抗性PCa的发展而复发。大量研究表明，细胞雄激素受体水平的下调，包括抑制其转录和促进其蛋白降解，对PCa细胞是致命的。在这里，我们报道了Aur阻滞细胞周期进程并诱导PCa细胞凋亡。USP14和UCHL5与Aur的共抑制促进了LNcap和22RV1 PCa细胞中雄激素受体的泛素化和降解。我们的研究结果还表明，Aur降低了雄激素受体的mRNA水平。总之，我们的研究结果表明，Aur是一种有希望的临床转化治疗PCa的药物。
Auranofin (Aur) inhibits thioredoxin reductases and is also an inhibitor of 19S proteasome associated deubiquitinases, targeting USP14 and UCHL5. Androgen receptor is often over-expressed in prostate cancer (PCa) and is strongly linked to PCa growth and progression. Consequently, androgen deprivation therapy (ADT) that reduces androgen has been applied to treat androgen receptor-mediated PCa for decades. Nevertheless, most ADT treated patients experience relapse due to the development of the castration-resistant PCa. Numerous studies have shown that down-regulation of cellular androgen receptor level, including inhibiting its transcription and promoting its protein degradation, is lethal to PCa cells. Here we report that Aur arrested cell cycle progression and induced apoptosis of PCa cells. Co-inhibition of USP14 and UCHL5 with Aur facilitated the ubiquitination and degradation of androgen receptors in LNcap and 22RV1 PCa cells. Our results also show that Aur decreases the mRNA level of androgen receptors. In conclusion, our findings suggest that Aur is a promising agent for clinical translation to treat PCa.