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Blocking GRP/GRP-R signaling decreases expression of androgen receptor splice variants and inhibits tumor growth in castration-resistant prostate cancer
Translational Oncology ( IF 5 ) Pub Date : 2021-08-27 , DOI: 10.1016/j.tranon.2021.101213
Thomas C Case 1 , Alyssa Merkel 2 , Marisol Ramirez-Solano 3 , Qi Liu 3 , Julie A Sterling 2 , Renjie Jin 1
Affiliation  

Clinical management of castration-resistant prostate cancer (CRPC) resulting from androgen deprivation therapy (ADT) remains challenging. Many studies indicate that androgen receptor splice variants (ARVs) play a critical role in the development of CRPC, including resistance to the new generation of inhibitors of androgen receptor (AR) action. ARVs are constitutively active and lack the ligand-binding domain (LBD), thereby allowing prostate cancer (PC) to maintain AR activity despite therapies that target the AR (full-length AR; AR-FL). Previously, we have reported that long-term ADT increases the neuroendocrine (NE) hormone – Gastrin Releasing Peptide (GRP) and its receptor (GRP-R) expression in PC cells. Further, we demonstrated that activation of GRP/GRP-R signaling increases ARVs expression by activating NF-κB signaling, thereby promoting cancer progression to CRPC. Most importantly, as a cell surface protein, GRP-R is easily targeted by drugs to block GRP/GRP-R signaling. In this study, we tested if blocking GRP/GRP-R signaling by targeting GRP-R using GRP-R antagonist is sufficient to control CRPC progression. Our studies show that blocking GRP/GRP-R signaling by targeting GRP-R using RC-3095, a selective GRP-R antagonist, efficiently inhibits NF-κB activity and ARVs (AR-V7) expression in CRPC and therapy-induced NEPC (tNEPC) cells. In addition, blocking of GRP/GRP-R signaling by targeting GRP-R can sensitize CRPC cells to anti-androgen treatment (such as MDV3100). Further, preclinical animal studies indicate combination of GRP-R antagonist (targeting ARVs) with anti-androgen (targeting AR-FL) is sufficient to inhibit CRPC and tNEPC tumor growth.



中文翻译:

阻断 GRP/GRP-R 信号会降低雄激素受体剪接变体的表达并抑制去势抵抗性前列腺癌的肿瘤生长

雄激素剥夺疗法 (ADT) 导致的去势抵抗性前列腺癌 (CRPC) 的临床管理仍然具有挑战性。许多研究表明,雄激素受体剪接变体 (ARV) 在 CRPC 的发展中起着关键作用,包括对新一代雄激素受体 (AR) 作用抑制剂的耐药性。ARV 具有组成型活性并且缺乏配体结合结构域 (LBD),因此尽管针对 AR(全长 AR;AR-FL)进行了治疗,但前列腺癌 (PC) 仍能保持 AR 活性。此前,我们曾报道长期 ADT 会增加神经内分泌 (NE) 激素 - 胃泌素释放肽 (GRP) 及其受体 (GRP-R) 在 PC 细胞中的表达。此外,我们证明了 GRP/GRP-R 信号的激活通过激活 NF-κB 信号来增加 ARV 的表达,从而促进癌症进展为 CRPC。最重要的是,作为一种细胞表面蛋白,GRP-R 很容易被药物靶向以阻断 GRP/GRP-R 信号传导。在这项研究中,我们测试了通过使用 GRP-R 拮抗剂靶向 GRP-R 来阻断 GRP/GRP-R 信号传导是否足以控制 CRPC 进展。我们的研究表明,通过使用 RC-3095(一种选择性 GRP-R 拮抗剂)靶向 GRP-R 来阻断 GRP/GRP-R 信号传导,可有效抑制 CRPC 和治疗诱导的 NEPC 中的 NF-κB 活性和 ARV (AR-V7) 表达。 tNEPC) 细胞。此外,通过靶向 GRP-R 阻断 GRP/GRP-R 信号可使 CRPC 细胞对抗雄激素治疗(如 MDV3100)敏感。此外,临床前动物研究表明 GRP-R 拮抗剂(靶向 ARV)与抗雄激素(靶向 AR-FL)的组合足以抑制 CRPC 和 tNEPC 肿瘤生长。

更新日期:2021-08-29
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