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 the LNCaP human prostate cancer (PCa) cell is mediated in large part by induction of insulin-like growth factor binding protein-3 (IGFBP-3). The purpose of this study was to determine the molecular mechanism involved in calcitriol regulation of IGFBP-3 and to identify the putative vitamin D response element (VDRE) in the IOFBP-3 promoter. We cloned 6 kb of the IGFBP-3 promoter and demonstrated its responsiveness to calcitriol in transactivation assays. Computer analysis identified a putative VDRE between -32961/-3282 that is similar to other known VDREs. In gel shift assays the vitamin D receptor (VDR) showed strong calcitriol-dependent binding to this putative VDRE. ChIP assay demonstrated that calcitriol recruited the VDR/RXR heterodimer to the VDRE site. In transactivation as says the VDRE promoter was induced 2-fold by calcitriol. Mutations created in the VDRE resulted in a loss of IGFBP-3 induction confirming the critical VDRE sequence. In conclusion, we have identified a functional VDRE in the distal region of the human IGFBP-3 promoter that directly mediates the action of calcitriol.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2004
- Accession Number
- ADA427982
Entities
People
- David Feldman
Organizations
- Stanford University