HSP70在与STUB1协作中的异构抑制可增强恩扎鲁胺在抗雄激素耐药前列腺肿瘤和患者源模型中的疗效。
Allosteric inhibition of HSP70 in collaboration with STUB1 augments enzalutamide efficacy in antiandrogen resistant prostate tumor and patient-derived models.
发表日期：2023 Feb 10
作者：
Pengfei Xu, Joy C Yang, Shu Ning, Bo Chen, Christopher Nip, Qiang Wei, Liangren Liu, Oleta T Johnson, Allen C Gao, Jason E Gestwicki, Christopher P Evans, Chengfei Liu
来源：
PHARMACOLOGICAL RESEARCH
摘要：
泛素蛋白酶体活性在恩扎鲁胺耐药的前列腺癌细胞中被抑制，热休克蛋白70/STIP1同源和U-box-containing蛋白1 (HSP70/STUB1)机制参与了雄激素受体 (AR) 和 AR 变异蛋白的稳定。针对 HSP70 可能是克服晚期前列腺癌雄激素受体信号抑制剂 (ARSI) 抵抗的可行策略。在这里，我们展示了一种新的 HSP70 变构抑制剂 JG98 显著抑制了耐药的 C4-2B MDVR 和 CWR22Rv1 细胞的生长，并增强了恩扎鲁胺的治疗效果。JG98 还抑制了从晚期前列腺癌患者样本中衍生的条件重编程细胞培养 (CRC) 和器官样。在机制上，JG98 降解了耐药细胞中的 AR/AR-V7 表达，并促进了 STUB1 核转位结合 AR-V7。 STUB1 的 E3 连接酶敲低显著减弱了 JG98 的抗癌效果，并部分恢复了 AR-V7 的抑制效果。JG98 衍生的更强效类似物 JG231 有效抑制了耐药性前列腺癌细胞、CRC 和器官样的生长。值得注意的是，JG231 和恩扎鲁胺的联合治疗协同抑制了 AR/AR-V7 的表达，并抑制了 CWR22Rv1 移植瘤的生长。使用新型小分子抑制剂抑制 HSP70 可以与 STUB1 协调调节 AR/AR-V7 蛋白稳定和 ARSI 抗药性。 版权所有 © 2023 作者。由 Elsevier Ltd. 发表。版权所有。
Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4-2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.