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/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.

• Authors: Asadur Rahman, Makoto Matsuyama, Akio Ebihara, Yuki Shibayama, Arif Ul Hasan, Hironori Nakagami, Fumiaki Suzuki, Jiao Sun, Tomoe Kobayashi, Hiroki Hayashi, Daisuke Nakano, Hideki Kobara, Tsutomu Masaki, Akira Nishiyama
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 9 Pg. 1844-1855 (09 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32669314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• ATP6AP2 protein, human
• Antibodies, Monoclonal
• Antineoplastic Agents, Immunological
• Receptors, Cell Surface
• Vacuolar Proton-Translocating ATPases

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antineoplastic Agents, Immunological (administration & dosage, pharmacology)
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• Humans
• Male
• Mice
• Pancreatic Neoplasms (drug therapy, metabolism)
• Protein Domains
• Rats
• Receptors, Cell Surface (antagonists & inhibitors, chemistry)
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors, chemistry)
• Wnt Signaling Pathway (drug effects)
• Xenograft Model Antitumor Assays