We previously reported that silencing of the PRR gene, which encodes the (pro)renin receptor [(P)RR], significantly reduced Wnt/β-catenin–dependent development of pancreatic ductal adenocarcinoma (PDAC). Here, we examined the effects of a panel of blocking mAbs directed against the (P)RR extracellular domain on proliferation of the human PDAC cell lines PK-1 and PANC-1 in vitro and in vivo. We observed that four rat anti-(P)RR mAbs induced accumulation of cells in the G0–G1-phase of the cell cycle and significantly reduced proliferation in vitro concomitant with an attenuation of Wnt/β-catenin signaling. Systemic administration of the anti-(P)RR mAbs to nude mice bearing subcutaneous PK-1 xenografts significantly decreased tumor expression of active β-catenin and the proliferation marker Ki-67, and reduced tumor growth. In contrast, treatment with the handle region peptide of (pro)renin did not inhibit tumor growth in vitro or in vivo, indicating that the effects of the anti-(P)RR mAbs were independent of the renin–angiotensin system. These data indicate that mAbs against human (P)RR can suppress PDAC cell proliferation by hindering activation of the Wnt/β-catenin signaling pathway. Thus, mAb-mediated (P)RR blockade could be an attractive therapeutic strategy for PDAC.

中文翻译：

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抗（原）肾素受体单克隆抗体在胰腺导管腺癌中的抗增殖作用

我们之前报道过，编码（原）肾素受体 [(P)RR] 的 PRR 基因的沉默显着降低了胰腺导管腺癌 (PDAC) 的 Wnt/β-连环蛋白依赖性发展。在这里，我们检查了一组针对 (P)RR 胞外域的阻断性 mAb 对体外和体内人 PDAC 细胞系 PK-1 和 PANC-1 增殖的影响。我们观察到四种大鼠抗 (P)RR mAb 在细胞周期的 G0-G1 期诱导细胞积累，并显着降低体外增殖，同时减弱 Wnt/β-连环蛋白信号传导。将抗 (P)RR mAb 全身给药至带有皮下 PK-1 异种移植物的裸鼠可显着降低活性 β-连环蛋白和增殖标志物 Ki-67 的肿瘤表达，并减少肿瘤生长。相比之下，用（原）肾素的手柄区肽处理体外或体内均未抑制肿瘤生长，表明抗（P）RR mAb 的作用与肾素-血管紧张素系统无关。这些数据表明，针对人 (P)RR 的 mAb 可以通过阻碍 Wnt/β-catenin 信号通路的激活来抑制 PDAC 细胞增殖。因此，mAb 介导的 (P)RR 阻断可能是 PDAC 的一种有吸引力的治疗策略。