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lüll Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention Bartik L; Whitfield GK; Kaczmarska M; Lowmiller CL; Moffet EW; Furmick JK; Hernandez Z; Haussler CA; Haussler MR; Jurutka PWJ Nutr Biochem 2010[Dec]; 21 (12): 1153-61The 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 (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.|Animals[MESH]|Anticarcinogenic Agents/*pharmacology[MESH]|Caco-2 Cells[MESH]|Curcumin/*pharmacology[MESH]|Cytochrome P-450 CYP3A/metabolism[MESH]|Humans[MESH]|Ligands[MESH]|Lithocholic Acid/metabolism[MESH]|Nuclear Receptor Coactivator 1/metabolism[MESH]|Rats[MESH]|Receptors, Calcitriol/genetics/*metabolism[MESH]|Retinoid X Receptors/genetics/metabolism[MESH]|Steroid Hydroxylases/metabolism[MESH]|Transcriptional Activation[MESH]|Two-Hybrid System Techniques[MESH]|Up-Regulation[MESH]|Vitamin D/*analogs & derivatives/genetics/metabolism[MESH]|Vitamin D3 24-Hydroxylase[MESH] |