Pharmacological inhibition of Ras-transformed epithelial cell growth is linked to down-regulation of epidermal growth factor-related peptides.
OBJECTIVE
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)-alpha and amphiregulin expression. Inhibition of proliferation of H-Ras RIE-1 cells by L744,832 was overcome by exogenous TGF-alpha, 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.
Sizemore
N
N
Departments of Medicine and Cell Biology, Vanderbilt University and Veterans Affairs Medical Center, Nashville, Tennessee, USA.
Cox
A D
AD
Barnard
J A
JA
Oldham
S M
SM
Reynolds
E R
ER
Der
C J
CJ
Coffey
R J
RJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000166:cytology; D008024:Ligands; D017368:Protein Prenylation / Q000187:drug effects*; D051381:Rats; D018631:ras Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008024:Ligands; D066246:ErbB Receptors; D018631:ras Proteins