Antiproliferative Effects of Monoclonal Antibodies against (Pro)Renin Receptor in Pancreatic Ductal Adenocarcinoma

Abstract

We previously reported that silencing of the PRR gene, which encodes the (pro)renin receptor [(P)RR], significantly reduced Wnt/b-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 G 0 -G 1 -phase of the cell cycle and significantly reduced proliferation in vitro concomitant with an attenuation of Wnt/b-catenin signaling. Systemic administration of the anti-(P)RR mAbs to nude mice bearing subcutaneous PK-1 xenografts significantly decreased tumor expression of active b-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 reninangiotensin system. These data indicate that mAbs against human (P)RR can suppress PDAC cell proliferation by hindering activation of the Wnt/b-catenin signaling pathway. Thus, mAb-mediated (P)RR blockade could be an attractive therapeutic strategy for PDAC.

Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H

“…Moreover, the extracellular domain of (P)RR also has a molecular interaction with low-density lipoprotein receptor protein 6 (LRP6) and Frizzled 8 of Wnt receptor complex 12 . The activation of Wnt signalling pathway through this molecular interaction is related to the development of PDAC 7,13 , Glioma 14 . and colorectal cancer 15 .…”

(Pro)renin Receptor Is a Novel Independent Prognostic Marker in Invasive Urothelial Carcinoma of the Bladder

“…The role of PRR in cancer development and progression can also be supported by big data analysis from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data-bases in several malignancies [ 13 ], although further specific investigation is needed in UC. This clinical study opens the perspective to investigate development of novel therapies for UC based on neutralizing anti-PRR molecular antibodies to suppress Wnt/β-catenin signaling [ 22 ].…”

“…Very recently, the prognostic role of PRR immunohistochemical expression has been confirmed in colorectal, breast, prostate, pancreatic, and renal cancers [ 13 , 15 , 16 , 17 , 18 , 19 , 20 ]. Additionally, PRR has been used as a molecular target for cancer diagnosis using single-photon emission computed tomography [ 21 ], and a new therapeutic strategy based on monoclonal antibodies against PRR is currently being investigated in pancreatic neo-plasia [ 22 ].…”

The Soluble (Pro)Renin Receptor in Health and Diseases: Foe or Friend?

“…Accumulating evidence has already indicated a therapeutic potential of PRR for these cancers. PRR works as an upstream component and activator of wnt/β-catenin signaling to upgrade the development of various cancers (Kouchi M et al, 2017;Ohba K et al, 2020;Ohba K et al, 2014;Rahman A et al, 2020;Shibayama Y et al, 2015;Wang J et al, 2019;Zhao K et al, 2020). Plasma sPRR concentrations were found significantly higher in patients with pancreatic ductal adenocarcinoma (Shibayama Y et al, 2015), prostate cancer (Mohammad AH et al, 2019), or breast cancer (Mohammad AH et al, 2020) compared to the healthy specimen.…”