title: Identification of aryl hydrocarbon receptor as a putative Wnt/beta-catenin pathway target gene in prostate cancer cells.
abstract: Recent genetic and functional analyses have implicated the wnt/beta-catenin signaling pathway in prostate cancer (CaP) pathogenesis. Thus, there is much interest in understanding the consequences of wnt signaling in CaP; target gene expression is one important area of inquiry and is the focus of this report. Adenoviral-mediated overexpression of a mutant, hyperactive form of beta-catenin in CWR22-Rv1 CaP cells led to increased aryl hydrocarbon receptor (AhR, or dioxin receptor) and transmembrane protein 2 RNA transcript expression, as detected by cDNA-microarray analyses. Validating these results, reverse transcription-PCR assays demonstrated that in CWR22-Rv1 cells as well as in LAPC-4 CaP cells, increased putative target gene RNA expression occurs with transient overexpression of mutant beta-catenin, treatment of cells with lithium chloride, or with wnt3a-conditioned medium, three distinct modes of experimental wnt/beta-catenin pathway activation. This beta-catenin-associated expression of AhR and transmembrane protein 2 does not require de novo protein synthesis and may only involve a certain subset of CaP cell lines. Western and immunofluorescence analyses were undertaken to assess the relationship between the wnt/beta-catenin-stimulated increase in AhR transcripts and AhR protein expression; we provide evidence that an association exists whereby up-regulation of AhR RNA by wnt or beta-catenin is coupled with augmented AhR protein levels. Intriguingly, these studies also demonstrated that nuclear beta-catenin staining may not be a sole deciding factor when predicting the status of wnt/beta-catenin signaling in CaP cells. Finally, the extent to which wnt signaling may synergize with an environmental agonist of AhR (2,3,7,8-tetrachlorodibenzo-p-dioxin) to potentiate AhR transcriptional activity was examined. Considering previous work linking AhR to processes of development and carcinogenesis, our data may highlight one particular role for wnt/beta-catenin signaling in prostate tumor biology.
authors.affiliation: Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Chesire
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dunn
authors.forename: Charles M
authors.initials: CM
authors.lastname: Ewing
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007739:L Cells; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D018336:Receptors, Aryl Hydrocarbon; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin