ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling.
ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling.
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DOI：
10.1038/s41388-021-01914-2
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发表时间：
2021-09
期刊：
影响因子：
8
通讯作者：
Gao AC
中科院分区：
文献类型：
--
作者：
Liu C;Armstrong CM;Ning S;Yang JC;Lou W;Lombard AP;Zhao J;Wu CY;Yu A;Evans CP;Tepper CG;Li PK;Gao AC
利用第二代抗雄激素药物，如恩杂鲁胺（Enza）、阿比特龙（Abi）、阿帕鲁胺（Apal）和darolutamide （Daro）靶向雄激素信号传导，是治疗去势抵抗性前列腺癌（CRPC）的主要方法。虽然这些治疗最初是有效的，但耐药性经常发生。尽管接受了AR靶向治疗，但雄激素受体（AR）及其变体如AR- v7的持续表达有助于晚期CRPC患者的治疗耐药性和癌症进展。这凸显了阻断持续AR信号的新策略的必要性。在此，我们鉴定了一种新的AR/AR- v7降解物（ARVib），发现ARVib可以有效降解AR/AR- v7蛋白，并减弱AR/AR- v7下游靶基因在前列腺癌细胞中的表达。在机制上，ARVib通过HSP70/STUB1机制调节介导的泛素-蛋白酶体途径降解AR/AR- v7蛋白。ARVib抑制HSP70表达，促进STUB1核易位，其中STUB1与AR/AR- v7结合，促进其泛素化和降解。ARVib在体外和体内显著抑制耐药前列腺肿瘤生长并改善恩杂鲁胺治疗。这些数据表明，ARVib有潜力作为AR/AR- v7降解药物治疗耐药CRPC。
Targeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR-targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies blocking continued AR signaling. Here, we identify a novel AR/AR-V7 degrader (ARVib) and found that ARVib effectively degrades AR/AR-V7 protein and attenuates AR/AR-V7 downstream target gene expression in prostate cancer cells. Mechanistically, ARVib degrades AR/AR-V7 protein through the ubiquitin-proteasome pathway mediated by HSP70/STUB1 machinery modulation. ARVib suppresses HSP70 expression and promotes STUB1 nuclear translocation, where STUB1 binds to AR/AR-V7 and promotes its ubiquitination and degradation. ARVib significantly inhibits resistant prostate tumor growth and improves enzalutamide treatment in vitro and in vivo. These data suggest that ARVib has potential for development as an AR/AR-V7 degrader to treat resistant CRPC.
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影响因子：
4.8
作者：
Chen W;Mook RA Jr;Premont RT;Wang J
通讯作者：
Wang J
影响因子：
8.8
作者：
Ge Z;Leighton JS;Wang Y;Peng X;Chen Z;Chen H;Sun Y;Yao F;Li J;Zhang H;Liu J;Shriver CD;Hu H;Cancer Genome Atlas Research Network;Piwnica-Worms H;Ma L;Liang H
通讯作者：
Liang H
影响因子：
16.6
作者：
Liu C;Lou W;Yang JC;Liu L;Armstrong CM;Lombard AP;Zhao R;Noel ODV;Tepper CG;Chen HW;Dall'Era M;Evans CP;Gao AC
通讯作者：
Gao AC
影响因子：
50.3
作者：
Andersen, Raymond J.;Mawji, Nasrin R.;Sadar, Marianne D.
通讯作者：
Sadar, Marianne D.
Galeterone和VNPT55诱导AR/AR-V7的蛋白酶体降解，通过细胞色素C释放诱导明显的凋亡，并抑制了体内抑制castration抗性前列腺癌异种移植物的生长。
影响因子：
--
作者：
Kwegyir-Afful AK;Ramalingam S;Purushottamachar P;Ramamurthy VP;Njar VC
通讯作者：
Njar VC