We have recently discovered the potential involvement of angiotensin II type 2 receptor (AT2R) signaling in pancreatic cancer using AT2R deficient mice. To examine the involvement of AT2R expression in human PDAC, expressions of AT2R as well as the major angiotensin II receptor (type 1 receptor, AT1R) in human PDAC and adjacent normal tissue was evaluated by immunohistochemistry and real time PCR using surgically dissected human PDAC specimens. In immunohistochemical analysis, relatively strong AT1R expression was detected consistently in both normal pancreas and PDAC areas, whereas moderate AT2R expression was detected in 78.5% of PDAC specimens and 100% of normal area of the pancreas. AT1R, but not AT2R, mRNA levels were significantly higher in the PDAC area than in the normal pancreas. AT2R mRNA levels showed a negative correlation trend with overall survival. In cell cultures, treatment with a novel AT2R agonist significantly attenuated both murine and human PDAC cell growth with negligible cytotoxicity in normal epithelial cells. In a mouse study, administrations of the AT2R agonist in tumor surrounding connective tissue markedly attenuated growth of only AT2R expressing PAN02 murine PDAC grafts in syngeneic mice. The AT2R agonist treatment induced apoptosis primarily in tumor cells but not in stromal cells. Taken together, our findings offer clinical and preclinical evidence for the involvement of AT2R signaling in PDAC development and pinpoint that the novel AT2R agonist could serve as an effective therapeutic for PDAC treatment.
Keywords: AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; Ad-, adenoviral vector; Ang II, angiotensin II; BSA, bovine serum albumin; DMEM, Dulbecco`s modification of Eagle`s medium; FBS, fetal bovine serum; GFP, green fluorescent protein; HBSS, Hanks’ balanced salt solution; HIF-1, hypoxia inducible factor; Ki, association constant; PCR, polymerase chain reaction; PDAC, pancreatic ductal adenocarcinoma; PI3K, phosphatidylinositol-3 kinase; PLZF, promyelocytic leukemia zinc finger protein; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; VEGF, vascular endothelial growth factor; angiotensin II type 2 receptor (AT2R); apoptosis; cGMP, cyclic guanosine monophosphate; pancreatic ductal adenocarcinoma; selective AT2R agonist.