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Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor
- Source :
- Oncogene. 22:6183-6193
- Publication Year :
- 2003
- Publisher :
- Springer Science and Business Media LLC, 2003.
-
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.
- Subjects :
- Transcriptional Activation
Cancer Research
medicine.medical_specialty
Cell
MAP Kinase Kinase Kinase 1
Protein Serine-Threonine Kinases
Mice
Downregulation and upregulation
Epidermal growth factor
Gastrin-releasing peptide
Internal medicine
Tumor Cells, Cultured
Genetics
medicine
Animals
Humans
Epidermal growth factor receptor
Enzyme Inhibitors
Phosphorylation
Autocrine signalling
Molecular Biology
Mice, Knockout
Mitogen-Activated Protein Kinase 3
biology
Fibroblasts
Enzyme Activation
ErbB Receptors
Receptors, Bombesin
stomatognathic diseases
medicine.anatomical_structure
Endocrinology
Gastrin-Releasing Peptide
Head and Neck Neoplasms
Carcinoma, Squamous Cell
Cancer research
biology.protein
Mitogen-Activated Protein Kinases
Mitogens
Tyrosine kinase
Cell Division
hormones, hormone substitutes, and hormone antagonists
Signal Transduction
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....d0ff770e263869ffff6d0c0e0a5b9c17