Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor

Oncogene. 2003 Sep 18;22(40):6183-93. doi: 10.1038/sj.onc.1206720.

Abstract

Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-alpha) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-alpha and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Division / drug effects
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • ErbB Receptors / physiology
  • Fibroblasts
  • Gastrin-Releasing Peptide / pharmacology*
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • MAP Kinase Kinase Kinase 1*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogens / pharmacology*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Bombesin / metabolism
  • Signal Transduction
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • Enzyme Inhibitors
  • Mitogens
  • Receptors, Bombesin
  • Gastrin-Releasing Peptide
  • ErbB Receptors
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Map3k1 protein, mouse