Farnesyltransferase inhibitors reverse Ras-mediated inhibition of Fas gene expression.
Factors that govern host-tumor interaction play a critical role in tumor progression. In previous studies we have shown that oncogenic Ras inhibits the expression of Fas (CD95) and renders Ras-transformed cells resistant to Fas-induced death. We now demonstrate that culture of Ras-transformed cells in the presence of the farnesyltransferase inhibitor (FTI) LB42722 leads to up-regulation of Fas expression, both under basal growth conditions and in the presence of the inflammatory cytokines IFN-gamma and tumor necrosis factor alpha. This is manifested by an increase in fas mRNA, Fas cell surface expression, and Fas-induced apoptosis. Whereas FTI up-regulates expression of FAS in Ras-transformed cells, it inhibits the expression of vascular endothelial growth factor. Culture of Ras-transformed cells in the presence of the histone deacetylase inhibitor trichostatin A resulted in morphological reversion and G(1) arrest (as observed with FTI); however, no induction of Fas was observed. Furthermore, the effects of FTI on Fas-induced death were shown to be independent of RhoB. Therefore, inhibition of oncogenic Ras by FTI can result in two events that alter host-tumor interactions: up-regulation of Fas, rendering tumors more sensitive to immune cytotoxic effector cells, and down-reglation of VEGF, which may inhibit tumor angiogenesis.
Zhang
Bin
B
Greenebaum Cancer Center, University of Maryland Medical System, Baltimore, Maryland 21201, USA.
Prendergast
George C
GC
Fenton
Robert G
RG
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020743:rhoB GTP-Binding Protein / Q000502:physiology
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D019014:fas Receptor; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; D020743:rhoB GTP-Binding Protein