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 D 3 (1,25D) to regulate gene transcription. Recently, the secondary bile acid, lithocholate, 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 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 VDRexpressing 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.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…Curcumin is a vitamin D receptor agonist. Curcumin has recently been identified as a direct VDR agonist (Bartik et al, 2010;Menegaz et al, 2011), which, in view of the above mentioned, implies that curcumin could be used to compensate for the lack of 1a,25(OH) 2 D 3 signaling in certain cancer cells. In that respect, the range of effects that the VDR exerts depends on the structural conformation of the ligand, which defines whether the agonist binds to the genomic domain (Rochel et al, 2000) or the partially overlapping alternative binding pocket (Mizwicki et al, 2004).…”

“…By using radiolabeling, it was demonstrated that curcumin competes with 0.4 nM 1a,25(OH) 2 D 3 for VDR binding with a K i of 2.9 mM (Bartik et al, 2010) when assuming a K d of 10 210 M for the 1a,25(OH) 2 D 3 -VDR complex (Bouillon et al, 2008). Molecular docking studies revealed that the keto-enol isoform of curcumin, which adopts a planar geometry, shows a strong binding affinity for the VDR alternative binding pocket (Menegaz et al, 2011).…”

A Functional and Putative Physiological Role of Calcitriol in Patched1/Smoothened Interaction

“…The next day the cells were transfected with components of a mammalian two-hybrid (M2H) system for assaying the heterodimerization of VDR and RXR␣ (retinoic X receptor ␣) upon ligand binding (32). The firefly luciferase reporter vector (pFR-Luc), expression vectors encoding RXR␣ bait (pCMV-BD-RXR␣) and VDR prey (pCMV-AD-VDR) fusion constructs, and pRL-TK were transfected in a ratio of 50:5:5:1 using a 3:1 ratio of Rotifect:DNA (g) (Carl Roth).…”

Influence of Dietary Phytochemicals and Microbiota on Colon Cancer Risk

“…It has been reported that curcumin can bind to the vitamin D receptor and activate VDR target genes such as CYP3A4, CYP24, and TRPV6 in Caco-2 cells, which may be another mechanism of action for curcumin. 56 Because curcumin has been found to mediate many important cancer pathways, clinical trials for curcumin and cancer are currently underway. 54 …”