Identification of aryl hydrocarbon receptor as a putative wnt/β-catenin pathway target gene in prostate cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2004-04, Vol.64 (7), p.2523-2533
• Main Authors: CHESIRE, Dennis R, DUNN, Thomas A, EWING, Charles M, LUO, Jun, ISAACS, William B
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; beta Catenin; Biological and medical sciences; Cytoskeletal Proteins - genetics; Gene Expression Regulation, Neoplastic - genetics; Humans; L Cells (Cell Line); Male; Medical sciences; Mice; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Prostatic Neoplasms - genetics; Proto-Oncogene Proteins - genetics; Receptors, Aryl Hydrocarbon - agonists; Receptors, Aryl Hydrocarbon - biosynthesis; Receptors, Aryl Hydrocarbon - genetics; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Trans-Activators - genetics; Transcriptional Activation; Tumors; Wnt Proteins; Zebrafish Proteins
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-3309

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.