title: Angiotensin II induces vascular endothelial growth factor in pancreatic cancer cells through an angiotensin II type 1 receptor and ERK1/2 signaling.
abstract: Vascular endothelial growth factor (VEGF) is a crucial pro-angiogenic component in pancreatic ductal adenocarcinoma (PDA), and its high expression levels have been correlated with poor prognosis and early postoperative recurrence. We have recently shown that high levels of angiotensin II (AngII) type 1 receptor (AT1R) correlate and colocalize with VEGF in invasive PDA and that AngII induces VEGF expression in PDA cell lines. In this study, we explored the signaling mechanisms involved in the AngII-mediated VEGF induction and correlated AT1R and VEGF expression in noninvasive precursor lesions. An AT1R antagonist significantly (p<0.05) inhibited the AngII-mediated induction of VEGF messenger RNA and protein in all PDA cell lines. AngII-VEGF induction was inhibited by the tyrosine kinase inhibitor genistein, suggesting a mitogen-activated protein kinase signaling mechanism. AngII activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38 or c-Jun NH2-terminal MAP kinases. Inhibition of ERK1/2 activation reduced the AngII-induced VEGF synthesis. Immunohistochemical analysis of precursor lesions showed increased expression of AT1R in most ductal cells undergoing metaplasia. Pancreatic intraepithelial neoplasms showed more intense AT1R staining when compared to intraductal papillary mucinous neoplasms, which showed heterogeneous immunoreactivity. VEGF followed the same distribution pattern of AT1R in both lesions. AT1R expression in the premalignant pancreatic lesions suggests its involvement in tumor progression and angiogenesis. Our mechanistic findings provide the first insight into an AngII-initiated signaling pathway that regulates PDA angiogenesis. An AT1R-mediated VEGF induction suggests the possibility of AT1R blockade as a novel therapeutic strategy to control angiogenesis in PDA.
authors.affiliation: Department of Surgery, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA, USA.
authors.forename: Rathai
authors.initials: R
authors.lastname: Anandanadesan
authors.forename: Qiaoke
authors.initials: Q
authors.lastname: Gong
authors.forename: Galina
authors.initials: G
authors.lastname: Chipitsyna
authors.forename: Agnes
authors.initials: A
authors.lastname: Witkiewicz
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Hwyda A
authors.initials: HA
authors.lastname: Arafat
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D019808:Losartan / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000235:genetics*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D044139:Receptor, Angiotensin, Type 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012334:RNA, Neoplasm; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; D019833:Genistein; D019950:Mitogen-Activated Protein Kinase 1; D019808:Losartan