Resveratrol-induced gene expression profiles in human prostate cancer cells

Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 03/2005; 14(3):596-604. DOI: 10.1158/1055-9965.EPI-04-0398
Source: PubMed


The transhydroxystilbene resveratrol is found at high levels in red wine and grapes, and red wine consumption may be inversely associated with prostate cancer risk. To gain insights into the possible mechanisms of action of resveratrol in human prostate cancer, we did DNA microarray analysis of the temporal transcriptional program induced by treatment of the human prostate cancer cell line LNCaP with resveratrol.
Spotted DNA microarrays containing over 42,000 elements were used to obtain a global view of the effects of resveratrol on gene expression. Prostate-specific antigen (PSA) and androgen receptor (AR) expression were determined by Northern blot and immunoblot analyses. Cell proliferation was determined by the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay and cell cycle analysis by flow cytometry.
We observed time-dependent expression changes in >1,600 transcripts as early as 6 hours after treatment with resveratrol. Most striking was the modulation of a number of important genes in the androgen pathway including PSA and AR. Resveratrol also down-regulated expression of cell cycle and proliferation-specific genes involved in all phases of the cell cycle, induced negative regulators of proliferation, caused accumulation of cells at the sub-G1 and S phases of the cell cycle, and inhibited cell proliferation in a time- and dose-dependent manner.
Resveratrol produces gene expression changes in the androgen axis and cell cycle regulators that may underlie its putative anticancer activities in prostate cancer.

Download full-text


Available from: James D Brooks, Oct 10, 2015
28 Reads
  • Source
    • "The effects of stilbenes on the AR and androgen-responsive genes are complex. However, gene expression data suggest that the down-regulation of androgen-responsive genes is not solely due to decreased levels of the AR [56]. To our knowledge this is the first report showing that stilbenes like RSV and FIDAS are able to inhibit the dimerization of different AR-variants. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens. Methodology In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay. Results The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo. Conclusion RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors.
    PLoS ONE 06/2014; 9(6):e98566. DOI:10.1371/journal.pone.0098566 · 3.23 Impact Factor
    • "Microarray analyses have been previously performed for emodin, verbascoside, and resveratrol and a huge number of genes have been found to be regulated by treatment with these compounds [45–47, 72–74]. Together with the microarray data of the present investigation, these results further emphasize the multifactorial activity of natural products. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim. In the present study, we investigated the antiangiogenic properties of 59 plants used in traditional Korean medicine. Selected phytochemicals were investigated in more detail for their modes of action. Methods. A modified chicken-chorioallantoic-membrane (CAM) assay using quail eggs was applied to test for antiangiogenic effects of plant extracts. A molecular docking in silico approached the binding of plant constituents to the vascular endothelial growth factor receptors 1 and 2 (VEGFR1, VEGFR2). Microarray-based mRNA expression profiling was employed to correlate the 50% inhibition concentrations (IC50) of a panel of 60 NCI cell lines to these phytochemicals. Results. Extracts from Acer mono leaves, Reynoutria sachalniensis fruits, Cinnamomum japonicum stems, Eurya japonica leaves, Adenophora racemosa whole plant, Caryopteris incana leaves-stems, and Schisandra chinensis stems inhibited angiogenesis more than 50% in quail eggs. Selected phytochemicals from Korean plants were analyzed in more detail using microarray-based mRNA expression profiles and molecular docking to VEGFR1 and VEGFR2. These results indicate multifactorial modes of action of these natural products. Conclusion. The antiangiogenic activity of plants used in traditional Korean medicine implicates their possible application for diseases where inhibition of blood vessel formation is desired, for example, cancer, macular degeneration, diabetic retinopathy and others.
    Evidence-based Complementary and Alternative Medicine 07/2013; 2013:131306. DOI:10.1155/2013/131306 · 1.88 Impact Factor
  • Source
    • "Resveratrol , downregulating the expression of both genes , is known to cause an accumulation of cells at the sub - G1 and S phases of the cell cycle , and inhibits cell proliferation depending on time and dose in LNCaP prostate cancer cell lines ( Jones et al . 2005 ) . Moreover , the downregulation of CDK2 after resveratrol treatment in incubated embryonic cardiomyoblasts may explain the accumulation of cell populations in the G1 phase ( Leong et al . 2007 ) . Dexamethasone , on the other hand , increased the expres - sion of CDK1 and CDK2 in our qRT - PCR assay . These data do not support the red"
    [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that primarily attacks joints and is therefore a common cause of chronic disability and articular destruction. The hyperplastic growth of RA-fibroblast-like synoviocytes (FLSs) and their resistance against apoptosis are considered pathological hallmarks of RA. The natural antioxidant resveratrol is known for its antiproliferative and pro-apoptotic properties. This study investigated the effect of resveratrol on RA-FLS. RA-FLS were isolated from the synovium of 10 RA patients undergoing synovectomy or joint replacement surgery. RA-FLS were first stressed by pre-incubation with interleukin 1beta (IL-1β) and then treated with 100μM resveratrol for 24h. In order to evaluate the influence of resveratrol on the transcription of genes, a Gene Chip Human Gene 1.0 ST Array was applied. In addition, the effect of dexamethasone on proliferation and apoptosis of RA-FLS was compared with that of resveratrol. Gene array analysis showed highly significant effects of resveratrol on the expression of genes involved in mitosis, cell cycle, chromosome segregation and apoptosis. qRT-PCR, caspase-3/7 and proliferation assays confirmed the results of gene array analysis. In comparison, dexamethasone showed little to no effect on reducing cell proliferation and apoptosis. Our in vitro findings point towards resveratrol as a promising new therapeutic approach for local intra-articular application against RA, and further clinical studies will be necessary.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 11/2012; 20(3-4). DOI:10.1016/j.phymed.2012.09.020 · 3.13 Impact Factor
Show more