Document Detail

Blocking angiotensin II Type 1 receptor triggers apoptotic cell death in human pancreatic cancer cells.
MedLine Citation:
PMID:  20118823     Owner:  NLM     Status:  MEDLINE    
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.
Qiaoke Gong; Molly Davis; Galina Chipitsyna; Charles J Yeo; Hwyda A Arafat
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pancreas     Volume:  39     ISSN:  1536-4828     ISO Abbreviation:  Pancreas     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-06-21     Completed Date:  2010-10-07     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8608542     Medline TA:  Pancreas     Country:  United States    
Other Details:
Languages:  eng     Pagination:  581-94     Citation Subset:  IM    
Department of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
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MeSH Terms
Angiotensin II Type 1 Receptor Blockers / pharmacology*
Carcinoma, Pancreatic Ductal / metabolism*,  pathology
Caspase 3 / metabolism
Cell Line, Tumor
Losartan / pharmacology*
Pancreatic Neoplasms / metabolism*,  pathology
Proto-Oncogene Proteins c-bcl-2 / metabolism
Receptor, Angiotensin, Type 1 / metabolism*
Tumor Suppressor Protein p53 / genetics,  metabolism
bcl-2-Associated X Protein / metabolism
Reg. No./Substance:
0/Angiotensin II Type 1 Receptor Blockers; 0/BAX protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptor, Angiotensin, Type 1; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 114798-26-4/Losartan; EC 3.4.22.-/Caspase 3

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