Transformation of rat fibroblasts by TGF-beta and EGF induces sensitivity for intercellular induction of apoptosis.

During intercellular induction of apoptosis, TGF-beta-treated nontransformed fibroblasts induce apoptosis specifically in transformed fibroblasts. To test whether sensitivity to intercellular induction of apoptosis is causally related to the expression of the transformed phenotype, NRK 536 cells were reversibly transformed by TGF-beta / EGF- treatment and were tested for their sensitivity to intercellular induction of apoptosis. Cells that expressed the transformed phenotype after application of both cytokines exhibited sensitivity for intercellular induction of apoptosis, whereas cells treated with only one of the cytokines did not show the transformed phenotype and remained insensitive. Sensitivity to intercellular induction seems to be determined by extracellular generation of superoxide anions, as sensitive cells generated extracellular superoxide anions and intercellular induction of apoptosis in these cells was inhibited by SOD. These data demonstrated that the cytokine-determined transformed phenotype of fibroblasts controls their sensitivity for intercellular induction of apoptosis through induction of superoxide anion generation.