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Intracellular mechanisms mediating the anti-apoptotic action of gastrin

Saravanan Ramamoorthy1, Vinzenz Stepan, Andrea Todisco

  • 1Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA.

Biochemical and Biophysical Research Communications
|September 8, 2004
PubMed

Insights

Gastrin (G17) inhibits pancreatic cancer cell death by activating Akt. This occurs via CCKB receptors and calcium, leading to BAD and FOXO phosphorylation, ultimately inactivating transcription factors.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Gastrin (G17) previously shown to inhibit apoptosis in AR4-2J pancreatic adenocarcinoma cells.
  • Akt signaling pathway implicated in gastrin's anti-apoptotic effect.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which gastrin (G17) inhibits apoptosis in pancreatic cancer cells.
  • To identify the specific signaling pathways and molecules involved in gastrin-mediated Akt activation.

Main Methods:

  • Western blotting to measure Akt, BAD, and FOXO3 phosphorylation.
  • In vitro Akt kinase assays using recombinant BAD.
  • Luciferase reporter assays to assess forkhead transcription factor activity.
  • Use of CCKB receptor antagonist (D2) and calcium chelator (BAPTA-AM).

Main Results:

  • D2 and BAPTA-AM blocked G17-induced Akt phosphorylation, indicating CCKB receptor and calcium dependence.
  • G17 stimulated phosphorylation of BAD and FOXO3, key apoptosis regulators.
  • G17 inhibited forkhead transcription factor activity in a calcium-dependent manner.
  • PKC pathway was not involved in G17-induced Akt activation.

Conclusions:

  • Gastrin (G17) inhibits apoptosis in pancreatic cancer cells by activating Akt.
  • This activation is mediated by CCKB receptors and intracellular calcium, independent of PKC.
  • Downstream effects include BAD and FOXO phosphorylation, leading to the inactivation of forkhead transcription factors.

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