Vitamin D analogue EB1089-induced prostate regression is associated with increased gene expression of insulin-like growth factor binding proteins

Vitamin D analogues have an antiproliferative effect on prostate cancer cel ls in vitro and thus have been proposed as candidates for chemoprevention o f prostate cancer. Insulin-like growth factor (IGF)-I has been shown to pro tect cells from apoptosis and plays an essential role in normal prostate ph ysiology. We have studied the effects of the 1,25-dihydroxyvitamin D-3 anal ogue EB1089 on the IGF system in the prostate in vivo. Treatment of rats wi th EB1089 for 14 days caused a 25% decrease in ventral prostate weight. Apo ptosis was detected in prostate sections of EB1089-treated rats by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and histologic examination of hematoxylin/ eosin stained tissue sections i ndicated that secretory epithelial cells were flattened, a characteristic o f cells undergoing pressure-induced atrophy. Ventral prostate regression wa s associated with 15- to 25-fold increases in gene expression of IGF-bindin g proteins (IGFBPs)-2,-3,-4 and -5. We also observed a 40-fold increase in prostatic TGF-I mRNA levels in response to EB1089. Although we have previou sly shown that castration of rats leads to upregulation of IGFBPs in the ve ntral prostate, EB1089 treatment had no effect on serum levels of dihydrote stosterone or free testosterone. These results suggest that prostate regres sion induced by EB1089 may be related to alterations in availability of IGF -I as a result of increased production of IGFBPs.