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Farnesyltransferase Inhibitors Reverse Ras-mediated Inhibition of Fas Gene Expression

Greenebaum Cancer Center, University of Maryland Medical System, Baltimore, Maryland 21201 [B. Z., R. G. F.], and Glenolden Laboratory, DuPont Pharmaceuticals Co., Glenolden, Pennsylvania 19036 [G. C. P.]

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- and tumor necrosis factor . 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 G₁ 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.

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