Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention☆

Abstract 

The nuclear vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D₃ (1,25D) to regulate gene transcription. Recently, the secondary bile acid, lithocholate (LCA), was recognized as a novel VDR ligand. Using reporter gene and mammalian two-hybrid systems, immunoblotting, competitive ligand displacement and quantitative real-time PCR, we identified curcumin (CM), a turmeric-derived bioactive polyphenol, as a likely additional novel ligand for VDR. CM (10⁻⁵ M) activated transcription of a luciferase plasmid containing the distal vitamin D responsive element (VDRE) from the human CYP3A4 gene at levels comparable to 1,25D (10⁻⁸ M) in transfected human colon cancer cells (Caco-2). While CM also activated transcription via a retinoid X receptor (RXR) responsive element, activation of the glucocorticoid receptor (GR) by CM was negligible. Competition binding assays with radiolabeled 1,25D confirmed that CM binds directly to VDR. In mammalian two-hybrid assays employing transfected Caco-2 cells, CM (10⁻⁵ M) increased the ability of VDR to recruit its heterodimeric partner, RXR, and steroid receptor coactivator-1 (SRC-1). Real-time PCR studies revealed that CM-bound VDR can activate VDR target genes CYP3A4, CYP24, p21 and TRPV6 in Caco-2 cells. Numerous studies have shown chemoprotection by CM against intestinal cancers via a variety of mechanisms. Small intestine and colon are important VDR-expressing tissues where 1,25D has known anticancer properties that may, in part, be elicited by activation of CYP-mediated xenobiotic detoxification and/or up-regulation of the tumor suppressor p21. Our results suggest the novel hypothesis that nutritionally-derived CM facilitates chemoprevention via direct binding to, and activation of, VDR.

Abbreviations: CM, curcumin, CYP3A4, cytochrome P450-subfamily 3A polypeptide 4, Dex, dexamethasone, 1,25D, 1,25-dihydroxyvitamin D₃, GR, glucocorticoid receptor, GRE, glucocorticoid responsive element, LCA, lithocholate, Rex, RXR-specific ligand LG101305, RXR, retinoid X receptor, RXRE, retinoid X receptor responsive element, steroid receptor coactivator-1, SRC-1, VDR, nuclear vitamin D receptor, VDREs, vitamin D responsive elements

Keywords: Curcumin, Vitamin D receptor, Retinoid X receptor, Cancer prevention, Anticancer diet, Turmeric