Abstract

Transforming growth factor beta (TGFbeta) is a paracrine mediator of prostate epithelial cell apoptosis. In rodents, castration induces production of TGFbeta by stromal cells, which leads to apoptosis of epithelial cells. To identify potential mediators of this cell death pathway, we developed a model using DU145 cells, a tumorigenic human prostate epithelial cell line. We discovered that at low density, in low mitogen media, DU145 cells apoptose when treated with TGFbeta1. Prior to the onset of death, TGFbeta1 treatment downregulated the expression of the caspase inhibitor FLICE-like inhibitory protein (FLIP), at both the mRNA and protein level, suggesting a causal role between FLIP downregulation and cell death. To confirm the importance of FLIP in TGFbeta1-induced apoptosis, we employed small interfering RNA (siRNA) to silence FLIP expression. Doing so led to apoptosis, which is consistent with the hypothesis that FLIP prevents death in these cells. Furthermore, inhibition of caspase-8 by siRNA knockdown partially rescued the apoptotic effects of TGFbeta1, suggesting a role for death receptor signaling components in TGFbeta-mediated death of prostate epithelial cells.