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Epidermal growth factor receptor transactivation is implicated in IL-6-induced proliferation and ERK1/2 activation in

Nadège Poncet1, Johann Guillaume, Guy Mouchiroud

  • 1Centre de Génétique Moléculaire et Cellulaire, UMR 5534, CNRS, Université Lyon 1, 43 boulevard du 11 novembre 1918, 69622 Villeurbanne, France

Cellular Signalling
|November 30, 2010
PubMed

Insights

Interleukin-6 (IL-6) promotes prostate cell proliferation by activating epidermal growth factor receptor (EGF-R) through the shedding of its ligands, involving metalloproteases like ADAM10 and ADAM17.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Prostate Cancer Research

Background:

  • Epidermal growth factor receptor (EGF-R) is a receptor tyrosine kinase involved in cell signaling.
  • EGF-R can be activated by non-cognate ligands through transactivation, a process crucial in physiological and pathological conditions.
  • Understanding EGF-R transactivation mechanisms is vital for comprehending cellular responses, particularly in prostate epithelium.

Purpose of the Study:

  • To investigate the mechanism by which interleukin-6 (IL-6) stimulates proliferation and ERK1/2 activation in normal prostate epithelial cells.
  • To elucidate the role of EGF-R transactivation in IL-6-mediated cellular responses.
  • To identify the specific metalloproteases involved in the IL-6-induced shedding of EGF-R ligands.

Main Methods:

  • Utilized the RWPE-1 cell line as a model for non-transformed prostate epithelial progenitor cells.
  • Administered IL-6 and various inhibitors, including general matrix metalloprotease inhibitor (GM6001), dual ADAM10/ADAM17 inhibitor (GW280264X), ADAM10 inhibitor (GI254023X), and ADAM17 inhibitor (TAPI-2).
  • Assessed cell proliferation and ERK1/2 phosphorylation levels to determine the effects of IL-6 and inhibitors.

Main Results:

  • IL-6 treatment promoted cell proliferation and ERK1/2 activation in RWPE-1 cells when EGF-R kinase activity was intact.
  • GM6001 and GW280264X effectively blocked IL-6-induced proliferation and ERK1/2 phosphorylation, indicating metalloprotease involvement.
  • While specific inhibitors for ADAM10 and ADAM17 showed partial effects, their combination or cooperation with other metalloproteases is suggested in IL-6 signaling.

Conclusions:

  • IL-6 stimulates the shedding of EGF-R ligands via metalloprotease activity, leading to EGF-R transactivation in normal prostate epithelial cells.
  • This IL-6-driven EGF-R transactivation pathway may play a significant role in promoting cell proliferation, especially in the context of inflammatory prostate conditions.
  • The findings highlight a novel mechanism of crosstalk between IL-6 and EGF-R signaling in prostate epithelial cells, with implications for understanding prostate inflammation and proliferation.

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