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Castration-induced Apoptosis of Androgen-dependent Shionogi Carcinoma Is Associated with Increased Expression of Genes Encoding Insulin-like Growth Factor-binding Proteins¹

Lady Davis Research Institute of the Sir Mortimer B. Davis Jewish General Hospital and Departments of Oncology and Medicine, McGill University, Montreal, Quebec, H3T 1E2 Canada [T. N., M. P.], and Division of Urology, Vancouver General Hospital, University of British Columbia, British Columbia, V5Z 3J5 Canada [H. M., M. E. G.]

Insulin-like growth factor (IGF) I has well-characterized mitogenic and antiapoptotic effects that are essential for maintenance of the normal prostate and may be important during regression of the normal prostate and/or prostate tumors induced by androgen-targeting therapies for prostate cancer. IGF-I activity is modulated by IGF-binding proteins (IGFBPs). Here we examine IGFBP expression during regression of androgen-dependent Shionogi carcinoma tumors after castration. In this model, we observe a 90% reduction in Shionogi tumors by 10 days postcastration. Northern blotting of RNA from tumors collected at various times after castration indicates a rapid induction of IGFBP-5 concomitant with apoptotic regression of tumors, as detected by Apoptag staining of tumor sections after castration. IGFBP-5 mRNA was not detectable in tumors from control animals, but levels increased 120-fold in tumors 3 days after castration. The mRNAs for IGFBP-3 and -4 were abundant in Shionogi tumors from intact mice and decreased to 33% and 20% of control, respectively. Castration had no significant effect on IGFBP-2 expression. Treatment with calcium channel blockers inhibited castration-induced apoptosis and tumor regression and also significantly inhibited up-regulation of IGFBP-5 after castration. These data provide strong evidence for a functional role of IGFBP-5 expression in mediating the apoptosis induced by androgen deprivation in androgen-dependent neoplasia.

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