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Transforming growth factor alpha activates Ha-Ras in human pancreatic cancer cells with Ki-ras mutations

T Seufferlein1, J Van Lint, S Liptay

  • 1Department of Internal Medicine I, University of Ulm, Ulm, Germany. thomas.seufferlein@medizin.uni-ulm.de

Gastroenterology
|May 29, 1999
PubMed
Abstract

Insights

Transforming growth factor-alpha activates the Ha-Ras-ERK pathway, driving pancreatic cancer cell proliferation. Inhibiting this cascade offers potential new treatments for pancreatic tumors with Ras mutations.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Signaling

Background:

  • Pancreatic cancer often exhibits constitutively active Ki-Ras mutations.
  • Transforming growth factor-alpha (TGF-alpha) is a Ras-activating growth factor.

Purpose of the Study:

  • Identify signaling pathways mediating TGF-alpha-induced proliferation in pancreatic cancer cells.
  • Investigate the role of Ras and ERK in this process.

Main Methods:

  • Immune complex kinase assays for ERK1/-2 and p90(rsk) activation.
  • Luciferase reporter assays for AP-1 and E74 activation.
  • Ras activation assays and immunocytochemistry for Ha-Ras.
  • Assays for DNA synthesis and soft agar colony formation.

Main Results:

  • TGF-alpha activated ERK1/-2 via MEK-1, independent of PKC.
  • TGF-alpha induced Ras and Ha-Ras activation, confirmed by membrane translocation.
  • MEK-1 and Ras inhibition blocked TGF-alpha-stimulated proliferation and growth.

Conclusions:

  • The Ha-Ras-ERK cascade is crucial for TGF-alpha-induced growth in pancreatic cancer with Ki-ras mutations.
  • Targeting this cascade presents a potential therapeutic strategy for pancreatic tumors.

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