Pharmacological inhibition of Ras-transformed epithelial cell growth is linked to down-regulation of epidermal growth factor–related peptides
| Autor: | Sean M. Oldham, Adrienne D. Cox, Nywana Sizemore, Robert J. Coffey, John A. Barnard, Channing J. Der, Evangeline R Reynolds |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
medicine.medical_treatment
Protein Prenylation Down-Regulation Ligands Amphiregulin Epidermal growth factor medicine Animals Epidermal growth factor receptor Enzyme Inhibitors Intestinal Mucosa Autocrine signalling Cell Line Transformed Hepatology biology Cell growth Growth factor Gastroenterology Rats Cell biology ErbB Receptors Biochemistry ras Proteins biology.protein Protein farnesylation Cell Division Transforming growth factor |
| Zdroj: | Gastroenterology. 117:567-576 |
| ISSN: | 0016-5085 |
| DOI: | 10.1016/s0016-5085(99)70449-x |
| Popis: | Background & Aims: Posttranslational farnesylation is required for Ras activation. Farnesyl transferase inhibitors (FTIs) selectively block protein farnesylation and reduce the growth of many Ras-transformed cells in vitro and in vivo. Activated Ras transforms rat intestinal epithelial (RIE-1) cells by a mechanism distinct from NIH 3T3 fibroblasts in that an epidermal growth factor receptor (EGFR) autocrine loop contributes significantly to the Ras-transformed RIE-1 phenotype. Methods: The ability of FTIs to block growth of Ras-transformed RIE-1 cells was evaluated, and these results were correlated with decreased EGFR ligand production. Results: FTI L744,832 caused a selective, dose-dependent, reversible blockade in proliferation of H-Ras–transformed RIE-1 cells, whereas control cell lines, K-Ras–transformed cells, and activated raf-transfected RIE cells were unaffected. The growth-inhibitory effects of L744,832 correlated with loss of farnesylated H-Ras protein and a marked reduction in transforming growth factor (TGF)-α and amphiregulin expression. Inhibition of proliferation of H-Ras RIE-1 cells by L744,832 was overcome by exogenous TGF-α, and enhanced growth inhibition was achieved by EGFR blockade in combination with L744,832. Conclusions: These data suggest that one mechanism by which FTIs inhibit growth of H-Ras–transformed epithelial cells is by reducing Ras-induced EGFR ligand production. GASTROENTEROLOGY 1999;117:567-576 |
| Databáze: | OpenAIRE |
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