INHIBITION OF FAS (CD95) EXPRESSION AND FAS-MEDIATED APOPTOSIS BY ONCOGENIC RAS

The ras oncogene plays an important role in the multistep progression to cancer by activation of signal transduction pathways that contribut e to aberrant growth regulation. Although many of these effects are ce ll autonomous, the ras oncogene also regulates the expression of genes that alter host/tumor interactions. We now extend the mechanisms thro ugh which ras promotes tumor survival by demonstrating that oncogenic Ras inhibits expression of the fas gene and renders Ras-transformed ce lls resistant to Fas-induced apoptosis. A panel of Ras-transformed clo nes exhibited a marked inhibition in fas mRNA and Fas cell surface exp ression as compared with untransformed parental cell lines. Fas expres sion was induced by culture in the presence of IFN-gamma + tumor necro sis factor or; however, the maximal level attained in Ras transformant s was similar to 10-fold below the level of untransformed cells. Where as untransformed cells were sensitive to apoptotic death induced by cr oss-linking surface Fas (especially after cytokine treatment), pas-tra nsformed cells were very resistant to Fas-induced death even under the most stringent assay conditions. To demonstrate that this resistance was mediated by oncogenic Ras and not secondary genetic events, pools of Ras-transformed cells were generated using a highly efficient retro viral transduction technique. Transformed pools were assayed 6 days af ter infection and demonstrated a marked decrease in fas gene expressio n and Fas-mediated apoptosis, Oncogenic pas did not promote general re sistance to apoptosis, because ectopic expression of a fas cDNA in Ras -transformed cells restored sensitivity to Fas-induced apoptosis. Thes e data indicate that oncogenic Ras inhibits basal levels of expression of the fas gene, and although cytokine signal transduction pathways a re functional in these cells, the level of surface Fas expression rema ins below the threshold required for induction of apoptosis, These dat a identify a mechanism by which Ras-transformed cells may escape from host-mediated immune destruction.