Castration-induced apoptosis of androgen-dependent shionogi carcinoma is associated with increased expression of genes encoding insulin-like growth factor-binding proteins

Insulin-like growth factor (IGF) I has well-characterized mitogenic and ant iapoptotic effects that are essential for maintenance of the normal prostat e and may be important during regression of the normal prostate andlor pros tate tumors induced by androgen-targeting therapies for prostate cancer. IG F-1 activity is modulated by IGF-bindlng proteins (IGFBPs), sere we examine IGFBP expression during regression of androgen-dependent Shionogi carcinom a tumors after castration, In this model, we observe a 90% reduction in Shi onogi tumors by 10 days postcastration, Northern blotting of RNA from tumor s collected at various times after castration indicates a rapid induction o f IGFBP-5 concomitant with apoptotic regression of tumors, as detected by A poptag staining of tumor sections after castration, IGPBP-5 mRNA was not de tectable in tumors from control animals, but levels increased 120-fold in t umors 3 days after castration. The mRNAs for IGFBP-3 and -4 were abundant i n Shionogi tumors from intact mice and decreased to similar to 33% and simi lar to 20% of control, respectively. Castration had no significant effect o n IGFBP-2 expression. Treatment with calcium channel blockers inhibited cas tration-induced apoptosis and tumor regression and also significantly inhib ited up-regulation of IGFBP-5 after castration, These data provide strong e vidence For a functional role of IGFBP-5 expression in mediating the apopto sis induced by androgen deprivation in androgen-dependent neoplasia.