Angiotensin II Type 2 Receptor: A Novel Modulator of Inflammation in Pancreatic Ductal Adenocarcinoma through Regulation of NF-ΚB Activity
Ankit V. Gandhi
Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Galina `Chipitsyna
Department of Biomedical Sciences, University of New England, Biddeford, ME 04005, USA
Daniel Relles
Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Charles J. Yeo
Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
Hwyda A. Arafat *
Department of Biomedical Sciences, University of New England, Biddeford, ME 04005, USA
*Author to whom correspondence should be addressed.
Abstract
Aims: The aim of this study was to explore potential pro-inflammatory, pro-migratory and pro-invasive roles of angiotensin II type 2 receptor (AT2R) in pancreatic ductal adenocarcinoma (PDAC) cells.
Study Design: AT2R-specific agonist (CGP42112A, CGP), blocking antibody, or siRNA were interchangeably used to analyze functional impact of AT2R on PDAC cell proliferation, migration, and invasion.
Results: This study revealed that AT2R blockade reduced proliferation, migration and invasion of PDAC cells. Blocking AT2R significantly lowed the expression of oxidative-stress genes Nox1, Nox3, Nox4, and Nox5, and pro-invasive genes MMP-2, MMP-9, OPN, and α5-integrin. AT2R siRNA significantly downregulated the expression levels of pro-inflammatory IL-1beta, IFN-γ, iNOS, IL-6, IL-8, and IL-15 mRNA. Blocking AT2R also inhibited the intrinsic and angiotensin II (AngII) or CGP-mediated activation of NF-κB.
Conclusion: These findings demonstrate previously unknown pro-inflammatory, pro-migratory and pro-invasive effects of AT2R in PDAC cells. Our data suggest that one mechanism by which AT2R promote inflammation is through activation of constitutive and AngII-mediated NF-κB. Thus, AT2R blockade could be a novel therapeutic strategy to target multiple pathways that mediate PDAC carcinogenesis.
Keywords: Pancreatic Ductal Adenocarcinoma (PDAC), AngII, AT2R, inflammation, NF-κB