Vitamin D. Treatment of Prostate Cancer: The Inhibitory Role of IGFBP-3

Abstract : Calcitriol plays a critical role in maintaining mineral homeostasis but also exhibits antiproliferative activity in many cancers. We have shown that the antiproliferative actions of calcitriol in LNCaP human prostate cancer cells are mediated mainly by induction of insulin-like growth factor binding protein 3 (IGFBP-3). We also found that androgens increase expression of IGFBP-3 and cause a major enhancement of IGFBP-3 stimulation by calcitriol. The purpose of this study was to determine the molecular mechanisms involved in calcitriol and androgen regulation of IGFBP-3. We cloned 6 kb of the IGFBP-3 promoter and demonstrated its responsiveness to calcitriol and androgen in transactivation assays. Computer analysis identified a putative vitamin D response element (VDRE) and a potential androgen response element (ARE) in the IGFBP-3 promoter. We proved each to be inducible by calcitriol or androgen. Mutations created in the VDRE or ARE resulted in a loss of IGFBP-3 induction confirming the critical response element sequences. Chromatin immunoprecipitation assays demonstrated that calcitriol recruited VDR/RXR heterodimers to the VDRE site and androgen recruited the AR/AR homodimer to the ARE site. In conclusion, we have identified a functional VDRE and ARE in the human IGFBP-3 promoter that directly mediates the action of calcitriol and androgen to regulate IGFBP-3 expression.