Differential expression of genes induced by resveratrol in LNCaP cells: P53‐mediated molecular targets

Abstract

Prostate cancer prevention by key elements present in human nutrients derived from plants and fruits has been confirmed in various cell cultures and tumor models. Resveratrol (RE), a phytoalexin, induces remarkable inhibitory effects in prostate carcinogenesis via diverse cellular mechanisms associated with tumor initiation, promotion and progression. Earlier studies have shown that RE alters the expression of genes involved in cell cycle regulation and apoptosis, including cyclins, cdks, p53 and cdk inhibitors. However, most of the p53-controlled effects related to the role of RE in transcription either by activation or repression of a sizable number of primary and secondary target genes have not been investigated. Our study examined whether RE activates a cascade of p53-directed genes that are involved in apoptosis mechanism(s) or whether it modifies the androgen receptor and its co-activators directly or indirectly and induces cell growth inhibition. We demonstrate by DNA microarray, RT-PCR, Western blot and immunofluorescence analyses that treatment of androgen-sensitive prostate cancer cells (LNCaP) with 10 -5 M RE for 48 hr downregulates prostate-specific antigen (PSA), AR co-activator ARA 24 and NF-kB p65. Altered expression of these genes is associated with an activation of p53-responsive genes such as p53, PIG 7, p21Waf1-Cip1 , p300/CBP and Apaf-1. The effect of RE on p300/ CBP plays a central role in its cancer preventive mechanisms in LNCaP cells. Our results implicate activation of more than one set of functionally related molecular targets. At this point we have identified some of the key molecular targets associated with AR and p53 target genes. These findings point to the need for further extensive studies on AR coactivators, such as p300, its central role in post-translational modifications such as acetylation of p53 and/or AR by RE in a time-and dose-dependent manner at different stages of prostate cancer that will fully elucidate the role of RE as a chemopreventive agent for prostate cancer in humans. © 2003 Wiley-Liss, Inc. Key words: resveratrol; cDNA microarray; gene expression; p300/CBP; p53 signaling; Phenolic antioxidants attract increasing attention for their potential as cancer chemopreventive agents. 1-10 Resveratrol (RE), a phytoalexin present in grapes and berries, is one of the most promising agents for prostate cancer prevention. 11-18 RE has antioxidant and antimutagenic activities that induce phase II drugmetabolizing enzymes; it mediates anti-inflammatory effects and inhibits cyclooxygenase and hydroperoxidase functions. 19 -22 In vitro research and preclinical studies strongly support the anticancer effects of RE. RE induces cell cycle arrest, inhibits DNA synthesis and induces apoptosis in prostate cancer cells and thus holds great promise for development as a chemopreventive agent for prostate cancer. 17,[23][24][25][26][27][28][29][30] RE is strongly linked with androgen receptor regulation. Recent studies by Mitchell et al. 23 and Hsieh et al. 31 have shown that RE rep...

Resveratrol‐induced apoptosis in MCF‐7 human breast cancer cells involves a caspase‐independent mechanism with downregulation of Bcl‐2 and NF‐κB

“…50,51 Studies analyzing the effect of RES on cardiovascular disease have also shown that this molecule inhibits lipid peroxidation by a pathway that involves NF-kB inactivation. 52,53 Therefore, the apoptosis induced by RES in MCF-7 cells could be mediated by Bcl-2 through a PI3K-and NF-kB-dependent mechanism.…”

Edible flowers — antioxidant activity and impact on cell viability

“…Consequently, resveratrol can have a potent effect, even in low-doses, through the aryl hydrocarbon receptor [44] that plays an important role in cancer cells [45]. Resveratrol not only influences estrogen receptors, but down-regulates the nuclear factor-KB [46], another important therapeutic target. The nuclear factor-KB may even be influenced by gallic acid [47] (present in great amounts in T. pratensis), quercetin [48], (which was detected in T. repens) or coumaric acid [49] (present only in V. arvensis and A. schoenoprasum).…”

An Analogue of Resveratrol HS-1793 Exhibits Anticancer Activity Against MCF-7 Cells Via Inhibition of Mitochondrial Biogenesis Gene Expression

“…For instance, resveratrol-induced apoptosis has repeatedly been reported to be accompanied by increased caspase activity (Ferry et al, 2002;Kim et al, 2004;Wolter et al, 2001). In addition, resveratrol-induced apoptosis was shown to be associated with Bax mitochondrial translocation (Mahyar-Roemer et al, 2002), inhibition of AKT activity (Brownson et al, 2002), up-regulation of the oncogene suppressor p53 (Narayanan et al, 2003), and down-regulation of cyclin D1 (Joe et al, 2002). In other studies, resveratrol has been shown to act via c-Jun NH 2 -terminal kinase (JNK), as resveratrol-induced p53-dependent transcriptional activity and apoptosis were blocked upon expression of a dominant-negative mutant of JNK or upon disruption of JNK1 or JNK2.…”