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.
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Acknowledgements
This work was supported by EDRN grant (U01CA84968) to J R Grandis and J M Siegfried, NCI Lung cancer SPORE grant (P50CA90440 and R01CA79882) to J M Siegfried and Lung SPORE post-doctoral fellowship to V W Y Lui and S M Thomas.
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Lui, V., Thomas, S., Zhang, Q. et al. Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. Oncogene 22, 6183–6193 (2003). https://doi.org/10.1038/sj.onc.1206720
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DOI: https://doi.org/10.1038/sj.onc.1206720
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