Abstract

Resveratrol is a polyphenolic phytochemical found in fruits, nuts, and vegetables that contributes to the remarkable dietary effects of polyphenolic as inhibitors of aging and multiple aging related diseases. In addition, resveratrol has been extensively investigated as an inhibitor of inflammatory diseases including cancer; however, the underlying mechanisms of these chemotherapeutic effects of resveratrol are not completely understood. In cancer cells, resveratrol inhibits cell growth, survival, migration, and invasion, and many of the effects of resveratrol resemble those observed for bis-indole derived (CDIM) compounds that bind the pro-oncogenic nuclear receptor 4A1 (NR4A1, Nur77) and act as receptor antagonists. Using an isothermal titration calorimetry binding assay, we observed that resveratrol bound to the ligand binding domain of NR4A1 with a K_D value of 2.4 µM and a ΔG of -32.2 kJ/mol. Resveratrol also inhibited NR4A1-dependent transactivation in H460 and H1299 lung cancer cells, suggesting that resveratrol is an NR4A1 antagonist. This observation was confirmed in a series of functional (cell proliferation, survival, migration, and invasion) and gene expression assays in H460 and H1299 cells, showing that treatment with resveratrol mimicked the effects of NR4A1 knockdown and were similar to results of previous studies using CDIM/NR4A1 antagonists. These data indicate that applications of resveratrol may be more effective in patients that overexpress NR4A1, which is a negative prognostic factor for patients with some solid tumor-derived cancers.