Blocking Angiotensin II Type 1 Receptor Triggers Apoptotic Cell Death in Human Pancreatic Cancer Cells
- 1 July 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Pancreas
- Vol. 39 (5), 581-594
- https://doi.org/10.1097/mpa.0b013e3181c314cd
Abstract
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.Keywords
This publication has 37 references indexed in Scilit:
- Cancer Statistics, 2008CA: A Cancer Journal for Clinicians, 2008
- Angiotensin II Induces Vascular Endothelial Growth Factor in Pancreatic Cancer Cells Through an Angiotensin II Type 1 Receptor and ERK1/2 SignalingJournal of Gastrointestinal Surgery, 2008
- Antihypertensives as Novel Antineoplastics: Angiotensin-I-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Blockers in Pancreatic Ductal AdenocarcinomaJournal of the American College of Surgeons, 2007
- The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Induces Growth Inhibition and Enhances Gemcitabine-Induced Cell Death in Pancreatic CancerClinical Cancer Research, 2007
- Radiotherapy in the Adjuvant Management of Pancreatic AdenocarcinomaSeminars in Oncology, 2005
- Monoclonal antibodies targeting epidermal growth factor receptor and vascular endothelial growth factor with a focus on head and neck tumorsCurrent Opinion in Oncology, 2005
- The genetics of pancreatic cancerThe American Journal of Surgery, 2003
- A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platformVirchows Archiv, 2003
- High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporterCarcinogenesis: Integrative Cancer Research, 2002
- Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?The Lancet, 1998