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HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway

Maria E Ramos-Nino1, Steven R Blumen, Tara Sabo-Attwood

  • 1University of Vermont College of Medicine, Department of Pathology, 89 Beaumont Avenue HSRF#216, Burlington, VT 05405, USA. Maria.Ramos@uvm.edu

American Journal of Respiratory Cell and Molecular Biology
|September 18, 2007
PubMed

Insights

Hepatocyte growth factor (HGF) drives malignant mesothelioma (MM) growth via a novel pathway involving ERK5 and Fra-1. Inhibiting this pathway may offer new MM treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Hepatocyte growth factor (HGF) and its receptor c-Met are highly expressed in malignant mesotheliomas (MMs).
  • HGF/c-Met signaling may promote MM growth and survival.
  • Fos-related antigen 1 (Fra-1) was previously shown to inhibit c-Met expression in rat mesotheliomas.

Purpose of the Study:

  • To investigate the role of Fra-1 in HGF-induced proliferation in human MMs.
  • To elucidate the signaling pathway mediating HGF effects in MMs.

Main Methods:

  • Human MM cell lines were treated with HGF.
  • RNA silencing (knockdown) and overexpression of Fra-1 were performed.
  • Expression of Fra-1, ERK5, AKT, and MEK5 was analyzed at mRNA and protein levels.
  • Cell viability and proliferating cell nuclear antigen (PCNA) expression were assessed.
  • Stable MM cell lines with dominant-negative MEK5 (dnMEK5) were generated.

Main Results:

  • HGF increased Fra-1 levels and phosphorylation of ERK5 and AKT in some MM lines.
  • These effects were inhibited by a PI3K inhibitor (LY290042).
  • Fra-1 knockdown decreased HGF-dependent phosphorylation and Fra-1 expression.
  • Fra-1 overexpression blocked MEK5 expression.
  • dnMEK5 expression led to increased basal Fra-1 levels.
  • HGF-induced MM cell viability and PCNA expression were abolished by MEK5 or Fra-1 knockdown.

Conclusions:

  • HGF-induced MM cell proliferation and viability are mediated by a novel PI3K/ERK5/Fra-1 feedback pathway.
  • This pathway may explain the tumor-specific effects of c-Met inhibitors in MMs and other cancers.

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