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Resveratrol Is a Nuclear Receptor 4A1 (NR4A1) Ligand the Antagonizes NR4A1-Regulated Prooncogenic Pathways in Lung Cancers

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Resveratrol Is a Nuclear Receptor 4A1 (NR4A1) Ligand the Antagonizes NR4A1-Regulated Prooncogenic Pathways in Lung Cancers Resveratrol is a Nuclear Receptor 4A1 (NR4A1) Ligand the Antagonizes NR4A1-Regulated Prooncogenic Pathways in Lung Cancers Lei Zhang1, Kumaravel Mohankumar1, Gregory Martin1, and Stephen Safe1 1Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843 Abstract Methods A. C. Resveratrol (3,5,4’-trihydroxystilbene) is a polyphenolic phytochemical found in fruits, nuts, Ø Cell line: A549, H460 and H1299 non-small lung cancer cell lines were purchased and vegetables and there is evidence that this compound offers protection from several from American Type Culture Collection. human diseases including cancer. In cancer cell lines, resveratrol inhibits cell growth, survival, Ø Cell proliferation Assay: A549, H460, H1299 cells are seeded (2x104 per well) in migration/invasion and genes/pathways associated with these anticancer activities. Many of 96-well plates. A549 cells were maintained with DEME and 10% FBS. H460 and B. the same anticancer activities reported for resveratrol have previously been observed in this H1299 cells were maintained in RPMI 1640 and 10% FBS. Cells were allowed to laboratory using bis-indole derived nuclear receptor 4A1 (NR4A1) ligands that antagonize of attach for 24 hours. Then, the cells were treated at given concentrations with NR4A1-regulated pro-oncogenic pathways. Treatment of A549, H460, H1299 lung cancer cells appropriate media and 2.5% stripe FBS for 24, 48, and 72 hours. XTT cell viability with 50-125 µM resveratrol for 24, 48, 72 hours inhibited cell growth and IC50 values for kit that was purchased from Cell Signaling was applied to stain live cells after growth inhibition decreased with time. In addition, resveratrol inhibited the mTOR signaling treatment. Plates were read with the absorbance at wavelength 450 nm. pathway and other responses in lung cancer cells as previously observed for NR4A1 Ø Transactivation assay: Luciferase activity was determined in cells transfection Figure 4. (A) Resveratrol decreased expression of Bcl-2 a antagonists in the same cell lines. Therefore, we investigated the interactions of resveratrol performed with GAL4-NR4A1 (human)/GAL4-luc constructs and the values were prosurvival gene.(B) resveratrol decreased expression of with the ligand binding domain of NR4A1 in an assay that measures fluorescent quenching of TXNDC5, Sestrin 2 and IDH1 and induced expression of normalized against corresponding β-gal activity. phospho-AMPK. (C) Resveratrol inhibits mTOR signaling and a tryptophan residue in the NR4A1 ligand binding pocket. Resveratrol bound NR4A1 and the Ø Western blotting: Cells were lysed and whole-cell lysates were resolved in 10% its downstream gene S6PR and 4EBP1 expression. All of these responses are decreased after NR4A1 knockdown. KD value was 1.4 µM. H460 and H1299 lung cancer cells were transfected with the yeast Gal4- SDS-PAGE gels and proteins were transferred using PVDF membrane by wet NR4A1 fusion construct and UAS-luciferase which contains tandem Gal4 response elements, blotting followed by primary and secondary antibody incubation and detection and treatment with 125+150 µM resveratrol decreased transactivation. Thus, resveratrol using ECL reagent. directly bound NR4A1, inhibited NR4A1-dependent transactivation, inhibited cell growth and Ø Cell migration: The cells were scratched using a pipette tip when the cell mTOR signaling, and the role of NR4A1 in mediating the responses induced by resveratrol is reached around 95% confluence, and were further incubated with fresh medium currently being investigated. for 24 hrs. Results Figure 5. Resveratrol treatment decreases the migration ability of H460 and H1299 lung cancer cells in vitro. H460 and Introduction H1299 cells were treatment with 125 μM and 150 μM resveratrol for 24 hours and the mobility rates were observed via wound healing assays. A549 H1299 H460 24hrs 150 24hrs 48hrs 150 48hrs NR4A1 + 72hrs 150 24hrs 72hrs 48hrs * 100 * 72hrs Conclusion Extract 100 Resveratrol * * * * * * 100 * * * * * * * * * * * Ø Resveratrol inhibits both H460 and H1299 cell proliferation and survival at * * Cell Viability 50 Cell Viability 50 350 Cell Viability Resveratrol 50 concentration 125 and 150 μM. 300 0 0 0 Ø Neg. Ctrl 0.125% DMSO 50 75 100 125 Neg. Ctrl 0.125% DMSO 50 75 100 125 NR4A1 expression is inhibited by resveratrol in H460 and H1299 cells. Neg. Ctrl 0.125% DMSO 50 75 100 125 250 Kd = 1.4 µmol/L 2 Ø ROS TXNDC5 NR4A1 R = 0.99 Resveratrol induces apoptosis in H460 and H1299 cells by inhibiting expression 200 Figure 2. Resveratrol inhibits cell growth and survival. Results are expressed as mean ± SD for triplicates per treatment and significant (P<0.05) difference from control treatments are indicated (*). of Bcl-2. 150 Ø Resveratrol induces phospho-AMPK but inhibited TXNDC5, Sestrin2 and IDH1 Sestrin-2 Caspase-3 100 Bcl-2 expression. 50 Figure 3. Effects of NR4A1 H460 Cells Ligands on transactivation. Ø Resveratrol inhibits mTOR signaling and it also indicated by the decrease of 0 H1299 Cells AMPK Parp UAS-Luc+GAL4-NR4A1 UAS-Luc+GAL4-NR4A1 H460 and H1299 cells Gal4- 1.5 S6RP and 4EBP1 expression. Fluorescence Intensity Fluorescence 1.5 NR4A1 and UAS-luc reporter gene luciferase activity was Ø Resveratrol decreases the migration ability of H460 and H1299. mTOR 0 10 20 30 40 50 60 70 4EBP1 1.0 * determined after treatment Resveratrol, µmol/L 1.0 * with Resveratrol. Results are Ø All of these responses have previously been observed after knockdown of a * expressed as mean ± SD for NR4A1 antagonists. 0.5 NR4A1+Ligand, Uncorrected 0.5 * at least 3 replicate S6RP NR4A1+Ligand, Corrected Luciferase Activity Fold Luciferase Resveratrol Activity Fold Luciferase determinations for each treatment group and 0.0 0.0 DMSO (0.15%) Resv 125uM Resv 150uM DMSO (0.15%) Resv 125uM Resv 150uM significant (p<0.05) inhibition Figure 1. Directly binding of resveratrol NR4A1(LBD) Acknowledgement is indicated (*). This research was supported by Texas AgriLife, NIH P30-ES029067 and the Sid Kyle Chair endowment..
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