An apoptosis signaling pathway induced by the death domain of FADD selectively kills normal but not cancerous prostate epithelial cells

The adaptor protein FADD directly, or indirectly via another adaptor called TRADD, recruits caspase 8 to death receptors of the tumor necrosis factor receptor family. Consequentially, a dominant-negative mutant (FADD-DN, whic h consists only of the FADD death domain) that binds to receptors but canno t recruit caspase 8 has been widely used to inhibit apoptosis by various st imuli that work via death receptors, Here, we show that FADD-DN also has an other cell type- and cancer-dependent activity because it induces apoptosis of normal human prostate epithelial cells but not normal prostate stromal cells or prostate cancer cells. This activity is independent of FADD DN's a bility to bind to three known interacting proteins, Fas, TRADD or RIP sugge sting that it is distinct from FADD's functions at activated death receptor s, FADD-DN induces caspase activation in normal epithelial cells as demonst rated using a Fluorescence Resonance Energy Transfer assay that measures ca spase activity in individual living cells. However, caspase-independent pat hways are also implicated in FADD-DN-induced apoptosis because caspase inhi bitors were inefficient at preventing prostate cell death. Therefore, the d eath domain of FADD has a previously unrecognized role in cell survival tha t is epithelial-specific and defective in cancer cells. This FADD-dependent signaling pathway may be important in prostate carcinogenesis.