Role of the Caspase-8 Inhibitor FLIP in Androgen-Withdrawal Induced Death of Prostate Epithelium

摘要

Secretory prostatic epithelial cells undergo apoptosis in response to androgen deprivation. Similarly,metastatic prostate cancers, which resemble secretory epithelium, also undergo apoptosis following androgen deprivation. Recent evidence suggests that death receptor signaling is required for prostate epithelial cell death following androgen withdrawal. We sought to extend this observation by investigating the role of death receptor signaling components in models of prostate epithelial cell death. Preliminary experiments suggest that FLIP can inhibit apoptosis of prostate epithelial cells. FLIP is an enzymatically inactive version of pro-caspase-8 which negatively regulates cell death, apparently via a dominant- negative mechanism. Based on our preliminary data, we hypothesize that FLIP is a key regulator of prostate apoptosis in response to androgen withdrawal. To address our hypothesis we propose a systematic approach involving, sequentially, correlative (aim 1), functional (aim 2) and mechanistic (aims 3 and 4) experiments. The specific aims are: i) correlate the pattern of FLIP expression with prostate epithelial cell death; ii) assess the functional consequences of forced FLIP expression on prostate epithelial apoptosis; iii) determine which death receptor pathway is involved in prostate epithelial cell death and iv) determine if androgens regulate the level of FLIP expression at the level of gene transcription.