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

Vivian Wai Yan Lui, Sufi Mary Thomas, Qing Zhang, Abbey Lynn Wentzel, Jill Marie Siegfried, Joyce Yan Li, Jennifer Rubin Grandis

Research output: Contribution to journalArticle

71 Scopus citations

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-α) 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-α and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.

Original languageEnglish (US)
Pages (from-to)6183-6193
Number of pages11
JournalOncogene
Volume22
Issue number40
DOIs
StatePublished - Sep 18 2003
Externally publishedYes

Keywords

  • EGFR transactivation
  • G-protein-coupled receptor
  • GRPR
  • Head and neck cancer
  • TGF-α

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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