Curcumin: a novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention.
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 (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.
Department of Biochemistry and Molecular Biophysics, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA.
Leonid
L
Bartik
G Kerr
GK
Whitfield
Magdalena
M
Kaczmarska
Christine L
CL
Lowmiller
Eric W
EW
Moffet
Julie K
JK
Furmick
Zachary
Z
Hernandez
Carol A
CA
Haussler
Mark R
MR
Haussler
Peter W
PW
Jurutka
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D003474:Curcumin / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008095:Lithocholic Acid / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
D016588:Anticarcinogenic Agents; D008024:Ligands; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D014807:Vitamin D; D008095:Lithocholic Acid; C097949:1,25-dihydroxyvitamin D; D013250:Steroid Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065668:Vitamin D3 24-Hydroxylase; D056920:Nuclear Receptor Coactivator 1; D003474:Curcumin