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Blocking angiotensin II Type 1 receptor triggers apoptotic cell death in human pancreatic cancer cells

Qiaoke Gong1, Molly Davis, Galina Chipitsyna

  • 1Department of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

Pancreas
|February 2, 2010
PubMed
Abstract

Insights

Losartan, an angiotensin II type 1 receptor (AT1R) blocker, reduces pancreatic cancer cell survival and promotes apoptosis, regardless of p53 mutation status. This suggests AT1R blockade as a potential therapy for pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with high mortality.
  • Angiotensin II type 1 receptor (AT1R) signaling may play a role in PDA angiogenesis.
  • The p53 tumor suppressor gene is frequently mutated in PDA.

Purpose of the Study:

  • To evaluate the antiproliferative and proapoptotic effects of losartan, an AT1R blocker, on PDA cells.
  • To investigate these effects in PDA cells with different p53 mutation statuses (wild-type vs. mutated).

Main Methods:

  • Cell cycle analysis using flow cytometry.
  • Apoptosis assessment via Annexin V/TdT assays.
  • Gene and protein expression analysis using RT-PCR and Western blotting.
  • Caspase-3 activity and promoter activity assays.

Main Results:

  • Losartan dose-dependently decreased PDA cell survival and increased G1 cell cycle arrest.
  • Losartan upregulated pro-apoptotic proteins (p53, Bax) and downregulated anti-apoptotic proteins (Bcl-2, Bcl-xl).
  • Losartan activated caspase-3, with effects being caspase-3-dependent in mutated p53 cells.

Conclusions:

  • Losartan stimulates proapoptotic signaling pathways in PDA cells irrespective of p53 mutation status.
  • AT1R is involved in the apoptotic machinery of PDA cells.
  • AT1R blockade represents a potential therapeutic strategy for controlling PDA growth, especially given frequent p53 mutations.

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