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

Leonid Bartik, G. Kerr Whitfield, Magdalena Kaczmarska, Christine L. Lowmiller, Eric W. Moffet, Julie K. Furmick, Zachary Hernandez, Carol A. Haussler, Mark R. Haussler, Peter Jurutka

Research output: Contribution to journalArticle

90 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1153-1161
Number of pages9
JournalJournal of Nutritional Biochemistry
Volume21
Issue number12
DOIs
StatePublished - Dec 2010

Keywords

  • Anticancer diet
  • Cancer prevention
  • Curcumin
  • Retinoid X receptor
  • Turmeric
  • Vitamin D receptor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Nutrition and Dietetics
  • Clinical Biochemistry

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  • Cite this

    Bartik, L., Whitfield, G. K., Kaczmarska, M., Lowmiller, C. L., Moffet, E. W., Furmick, J. K., Hernandez, Z., Haussler, C. A., Haussler, M. R., & Jurutka, P. (2010). Curcumin: A novel nutritionally derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention. Journal of Nutritional Biochemistry, 21(12), 1153-1161. https://doi.org/10.1016/j.jnutbio.2009.09.012