OBJECTIVES: Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with an annual mortality rate close to its annual incidence. We recently demonstrated that angiotensin II (AngII) type 1 receptor (AT1R) might be involved in PDA angiogenesis. This study evaluated the antiproliferative and proapoptotic effects of an AT1R blocker, losartan, in PDA cells with different p53 mutation status. METHODS: Cell cycle was analyzed by flow cytometric analysis of DNA content; apoptosis by annexin V-fluorescein isothiocyanate (V-FITC) and terminal deoxytransferase (TdT)-mediated dUTP nick-end labeling staining; messenger RNA and protein by real-time polymerase chain reaction and Western blotting; caspase-3 activity by colorimetric assay; and promoter activity by luciferase assay. RESULTS: Losartan dose-dependently decreased cell survival and increased their preG1 accumulation. It also increased p53, p21, p27, and Bax and reduced Bcl-2 and Bcl-xl expression. In wtp53 cells, losartan increased p53 transcription and activated caspase-3 in both cell lines. However, its proapoptotic effects in mtp53 cells were mainly caspase-3-dependent. CONCLUSION: Our data describe the involvement of AT1R in PDA cell apoptotic machinery and provide the first evidences that losartan stimulates the proapoptotic signaling pathways regardless of the p53 mutation status. As loss of p53 function is frequently observed in PDA patients, our data suggest AT1R blockade as a novel therapeutic strategy to control PDA growth.
OBJECTIVES:Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with an annual mortality rate close to its annual incidence. We recently demonstrated that angiotensin II (AngII) type 1 receptor (AT1R) might be involved in PDA angiogenesis. This study evaluated the antiproliferative and proapoptotic effects of an AT1R blocker, losartan, in PDA cells with different p53 mutation status. METHODS: Cell cycle was analyzed by flow cytometric analysis of DNA content; apoptosis by annexin V-fluorescein isothiocyanate (V-FITC) and terminal deoxytransferase (TdT)-mediated dUTP nick-end labeling staining; messenger RNA and protein by real-time polymerase chain reaction and Western blotting; caspase-3 activity by colorimetric assay; and promoter activity by luciferase assay. RESULTS:Losartan dose-dependently decreased cell survival and increased their preG1 accumulation. It also increased p53, p21, p27, and Bax and reduced Bcl-2 and Bcl-xl expression. In wtp53 cells, losartan increased p53 transcription and activated caspase-3 in both cell lines. However, its proapoptotic effects in mtp53 cells were mainly caspase-3-dependent. CONCLUSION: Our data describe the involvement of AT1R in PDA cell apoptotic machinery and provide the first evidences that losartan stimulates the proapoptotic signaling pathways regardless of the p53 mutation status. As loss of p53 function is frequently observed in PDA patients, our data suggest AT1R blockade as a novel therapeutic strategy to control PDA growth.
Authors: Raimundo Fernandes de Araújo Júnior; Ana Luiza C S Leitão Oliveira; Raniere Fagundes de Melo Silveira; Hugo Alexandre de Oliveira Rocha; Pedro de França Cavalcanti; Aurigena Antunes de Araújo Journal: Exp Biol Med (Maywood) Date: 2014-08-14
Authors: Daniel Keizman; Peng Huang; Mario A Eisenberger; Roberto Pili; Jenny J Kim; Emmanuel S Antonarakis; Hans Hammers; Michael A Carducci Journal: Eur J Cancer Date: 2011-05-18 Impact factor: 9.162
Authors: Mazhar Al-Zoubi; Galina Chipitsyna; Shivam Saxena; Konrad Sarosiek; Ankit Gandhi; Christopher Y Kang; Daniel Relles; Jocelyn Andrelsendecki; Terry Hyslop; Charles J Yeo; Hwyda A Arafat Journal: J Gastrointest Surg Date: 2013-10-04 Impact factor: 3.452
Authors: Y Nakai; H Isayama; H Ijichi; T Sasaki; N Sasahira; K Hirano; H Kogure; K Kawakubo; H Yagioka; Y Yashima; S Mizuno; K Yamamoto; T Arizumi; O Togawa; S Matsubara; T Tsujino; K Tateishi; M Tada; M Omata; K Koike Journal: Br J Cancer Date: 2010-10-26 Impact factor: 7.640