Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer
Regulation and targeting of androgen receptor nuclear localization in castration-resistant prostate cancer
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DOI：
10.1172/jci141335
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发表时间：
2021-02-15
影响因子：
15.9
通讯作者：
Wang, Zhou
中科院分区：
文献类型：
--
作者：
Lv, Shidong;Song, Qiong;Wang, Zhou
雄激素受体（AR）的核定位是其作为转录因子激活所必需的。确定调节雄激素敏感细胞中AR核定位的机制以及这些机制在去势抵抗性前列腺癌（CRPC）细胞中如何失调是至关重要的和临床相关的。根据经典的AR细胞内运输模型，雄激素诱导AR核输入，雄激素戒断导致AR核输出。目前的研究已经导致了一个更新的模型，AR可以在雄激素的情况下输入，泛素化，并在细胞核中降解。雄激素戒断引起核AR降解，但不输出。与其亲本雄激素敏感性LNCaP前列腺癌细胞相比，去势抵抗C4-2细胞表现出减少的核AR聚泛素化和增加的核AR水平。我们先前在高通量筛选中鉴定了3-（4-氯苯基）-6，7-二氢-5H-吡咯并[1，2-a]咪唑（CPPI）对CRPC细胞中雄激素非依赖性AR核定位的抑制作用。目前的研究表明，CPPI是一种竞争性AR拮抗剂，能够增强AR与其E3连接酶MDM 2的相互作用，并降解CRPC细胞核中的AR。此外，CPPI阻断雄激素非依赖性AR核输入。总的来说，这些发现表明了用小分子抑制剂靶向雄激素非依赖性AR核输入和稳定化的可行性，这是导致CRPC细胞中AR核定位和活化的两个必要步骤。
Nuclear localization of the androgen receptor (AR) is necessary for its activation as a transcription factor. Defining the mechanisms regulating AR nuclear localization in androgen-sensitive cells and how these mechanisms are dysregulated in castration-resistant prostate cancer (CRPC) cells is fundamentally important and clinically relevant. According to the classical model of AR intracellular trafficking, androgens induce AR nuclear import and androgen withdrawal causes AR nuclear export. The present study has led to an updated model that AR could be imported in the absence of androgens, ubiquitinated, and degraded in the nucleus. Androgen withdrawal caused nuclear AR degradation, but not export. In comparison with their parental androgen-sensitive LNCaP prostate cancer cells, castration-resistant C4-2 cells exhibited reduced nuclear AR polyubiquitination and increased nuclear AR level. We previously identified 3-(4-chlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a] imidazole (CPPI) in a high-throughput screen for its inhibition of androgen-independent AR nuclear localization in CRPC cells. The current study shows that CPPI is a competitive AR antagonist capable of enhancing AR interaction with its E3 ligase MDM2 and degradation of AR in the nuclei of CRPC cells. Also, CPPI blocked androgen-independent AR nuclear import. Overall, these findings suggest the feasibility of targeting androgen-independent AR nuclear import and stabilization, two necessary steps leading to AR nuclear localization and activation in CRPC cells, with small molecule inhibitors.