Androgen regulation of FLICE-like inhibitory protein gene expression in the rat prostate

In hope of eventually identifying defects in human prostatic neoplasias that render them insensitive to anti-androgen therapy, we have examined the regulation of components of ligand-induced cell death pathways during castration-induced regression of the prostate. Rat prostates were obtained after surgical castration with or without subsequent androgen replacement. The mRNA levels of genes encoding components of the apoptotic pathway were measured from individual prostates. Whole prostates 1-10 days after castration did not show a significant change in mRNA levels encoding either Fas or FasL, which some studies suggest are necessary for regression to occur. However, the mRNA encoding a catalytically inactive cysteinyl aspartate-specific protease (caspase) analog, FLICE-like inhibitor protein (FLIP), decreases during the first day following castration. In the most apoptotically responsive ventral lobe of the rat prostate, the reduction in FLIP mRNA levels is evident within 12 h of castration. The mRNA levels of the principal target of FLIP inhibition, caspase-8, do not change during the period preceding the onset of detectable DNA fragmentation. Androgen administration to castrated rats reverses prostate regression, and restores FLIP mRNA to normal levels. By acting as an inhibitor of caspase-8, FLIP may protect prostatic epithelium from apoptosis. Androgen withdrawal, by reducing FLIP mRNA levels, might leave the cells vulnerable to as yet unidentified cell death signals.