Resveratrol potentiates vitamin D and nuclear receptor signaling.

The 1,25-dihydroxyvitamin D3 (1,25D) hormone is derived from vitamin D generated in skin or obtained from the diet, and binds to and activates the vitamin D receptor (VDR) in target tissues including kidney, colon/small intestine, and bone/muscle. We tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (VDRE) and mammalian 2-hybrid (M2H) transcriptional system technology. Via VDRE-based assays in kidney, colon and myoblast cells, VDR-mediated transcription was activated by resveratrol, and a cooperative effect on transactivation was observed with resveratrol plus 1,25D. The M2H assay revealed a modest, resveratrol-induced dimerization of VDR with its retinoid X receptor (RXR) heteropartner. Cells treated with both resveratrol and 1,25D displayed synergistic stimulation of VDR-RXR heterodimerization, while resveratrol antagonized rexinoid-mediated RXR-RXR homodimerization. Increased transactivation in response to resveratrol was also observed with a subset of other nuclear receptors and their respective cognate responsive elements. Evaluation of wild-type versus a ligand-binding domain mutant VDR revealed that hormone-responsiveness to 1,25D was severely depressed, while the response to resveratrol was only moderately attenuated. Moreover, radiolabeled 1,25D-displacement assays demonstrated an increase in VDR-bound 1,25D in the presence of resveratrol. Thus, resveratrol may affect VDR and other nuclear receptors indirectly, likely via the ability of resveratrol to: (1) potentiate 1,25D binding to VDR; (2) activate RXR; and/or (3) stimulate SIRT1, an enzyme known to deacetylate nuclear receptors. The results of this study elucidate a possible pathway for crosstalk between two nutritionally derived lipids, vitamin D and resveratrol, both of which converge on VDR signaling.

Synthesis and biological evaluation of halogenated curcumin analogs as potential nuclear receptor selective agonists.

This report describes the synthesis of analogs of curcumin, and their analysis in acting as nuclear receptor specific agonists. Curcumin (CM), a turmeric-derived bioactive polyphenol found in curry, has recently been identified as a ligand for the vitamin D receptor (VDR), and it is possible that CM exerts some of its bioeffects via direct binding to VDR and/or other proteins in the nuclear receptor superfamily. Using mammalian-two-hybrid (M2H) and vitamin D responsive element (VDRE) biological assay systems, we tested CM and 11 CM synthetic analogs for their ability to activate VDR signaling. The M2H assay revealed that RXR and VDR association was induced by CM and several of its analogs. VDRE-based assays demonstrated that pure curcumin and eight CM analogs activated transcription of a luciferase plasmid at levels approaching that of the endocrine 1,25 dihydroxyvitamin D(3) (1,25D) ligand in human colon cancer cells (HCT-116). Additional experiments were performed in HCT-116 utilizing various nuclear receptors and hormone responsive elements to determine the receptor specificity of curcumin binding. CM did not appear to activate transcription in a glucocorticoid responsive system. However, CM along with several analogs elicited transcriptional activation in retinoic acid and retinoid X receptor (RXR) responsive systems. M2H assays using RXR-RXR, VDR-SRC1 and VDR-DRIP revealed that CM and select analogs stimulate RXR homodimerization and VDR-coactivator interactions. These studies may lead to the discovery of novel curcumin analogs that activate nuclear receptors, including RXR, RAR and VDR, resulting in similar health benefits as those for vitamins A and D, such as lowering the risk of epithelial and colon cancers.