The Wilms tumor suppressor gene WT1 encodes a developmentally regulated transcription factor that is mutated in a subset of embryonal tumors. To test its functional properties, we developed osteosarcoma cell lines expressing WT1 under an inducible tetracycline‐regulated promoter. Induction of WT1 resulted in programmed cell death. This effect, which was differentially mediated by the alternative splicing variants of WT1, was independent of p53. WT1‐mediated apoptosis was associated with reduced synthesis of the epidermal growth factor receptor (EGFR), but not of other postulated WT1‐target genes, and it was abrogated by constitutive expression of EGFR. WT1 repressed transcription from the EGFR promoter, binding to two TC‐rich repeat sequences. In the developing kidney, EGFR expression in renal precursor cells declined with the onset of WT1 expression. Repression of EGFR and induction of apoptosis by mechanism that may contribute to its critical role in normal kidney development and to the immortalization of tumor cells with inactivated WT1 alleles.

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Wilms tumor is a pediatric neoplasm that arises from the metanephric blastema.

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...