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Androgen regulated genes in prostate cancer cells Cochrane, Dawn Renee

Abstract

Prostate cancer is a leading cause of cancer death in Canadian men. Prostate tumors initially depend on androgens for survival and androgen ablation is an effective therapy. Prostate cancer adapts to the androgen depleted environment and begins to grow in an androgen independent (Al) form. Androgens exert their effects through the action of the androgen receptor (AR), a ligand dependent transcription factor. AR is important for cell survival and appears central to the progression of prostate cancer to Al. The hypothesis driving the present studies is that androgen regulated genes are reactivated during prostate cancer progression to Al and as such, identification of novel androgen regulated genes will provide new targets for which therapeutics can be directed. To discover novel androgen regulated genes, cultured prostate cells were treated with androgens and an expression profile generated using a microarray screen. Validation of the microarray experiment revealed the upregulation of genes involved in cell survival (GADD45G), development of drug resistance (MRP4) and protection against oxidative stress (NFE2L2), while a pro-apoptotic gene (BARD1) was down regulated. Probing a tissue microarray, GADD45G was found upregulated in Al prostate cancer. In vitro studies revealed that GADD45G is important for cell survival and acts as a control point for several critical intracellular signaling cascades. One surprising result was that while GADD45G mRNA levels increase with androgens, protein levels decrease. A miRNA, hsa-miR-326 was found to be responsible for inhibition of GADD45G translation and this inhibition could be relieved under stress conditions such as treatment with high levels of taxol. Clusterin, a gene involved in apoptosis, has two isoforms resulting from alternate transcriptional start sites and these were found to be differentially regulated by androgens. Initial transcripts of both isoforms encode an anti-apoptotic protein; however Isoform 1 can be spliced into a pro-apoptotic form, while Isoform 2 cannot. Isoform 1 was found to be repressed by androgens while Isoform 2 is upregulated, consistent with androgens being cytoprotective in prostate cells. The work presented here highlights the importance of androgen regulated genes in prostate cancer survival and identifies GADD45G and clusterin as being potential targets for therapeutics.

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