ras oncogene expression determines sensitivity for intercellular inductionof apoptosis

Fibroblasts carrying an inducible ras oncogene acquire the transformed phen otype after oncogene induction. As a consequence, the transformed cells bec ome sensitive to intercellular induction of apoptosis, a novel regulatory p rocess directed by non-transformed fibroblasts against their transformed de scendants. The causal relationship between oncogene expression and sensitiv ity to intercellular induction of apoptosis is based on extracellular super oxide anion production by oncogene-expressing cells. Superoxide anions (aft er dismutation to hydrogen peroxide) thereby foster HOCl synthesis and at t he same time direct the selectivity of apoptosis induction through hydroxyl generation from HOCl. In parallel, ras expression enhances the sensitivity of fibroblasts for apoptosis-inducing stimuli like cycloheximide, ceramide and mitomycin C. This sensitization seems to be based on a decreased conce ntration of short lived endogenous apoptosis inhibitors. TGF-beta, like ras induction, decreases the concentration of endogenous apoptosis inhibitors, but does not induce the transformed phenotype. Therefore, TGF-beta treatme nt alone is not sufficient to render fibroblasts sensitive for intercellula r induction of apoptosis, but TGF-beta treatment in parallel with ras activ ation enhances intercellular induction of apoptosis. Our findings demonstra te that Ras-mediated superoxide anion production determines sensitivity to intercellular induction of apoptosis, whereas the parallel decrease in endo genous apoptosis inhibitors modulates the kinetics of apoptosis induction.