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Identification of Aryl Hydrocarbon Receptor as a Putative Wnt/ß-Catenin Pathway Target Gene in Prostate Cancer Cells

¹ Brady Urological Institute, ² Johns Hopkins Oncology Center, Johns Hopkins Medical Institutions, Baltimore, Maryland

Recent genetic and functional analyses have implicated the wnt/ß-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 ß-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 ß-catenin, treatment of cells with lithium chloride, or with wnt3a-conditioned medium, three distinct modes of experimental wnt/ß-catenin pathway activation. This ß-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/ß-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 ß-catenin is coupled with augmented AhR protein levels. Intriguingly, these studies also demonstrated that nuclear ß-catenin staining may not be a sole deciding factor when predicting the status of wnt/ß-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/ß-catenin signaling in prostate tumor biology.

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