Selenium molecular signaling in human prostate cancer

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DESCRIPTION (provided by applicant): Scanty information is currently available on the molecular mechanism of selenium chemoprevention in prostate cancer. Preliminary studies showed that physiological concentrations of a selenium metabolite inhibited the growth of both the androgen-responsive LNCaP and the androgen-nonresponsive PC-3 human prostate cancer cells. Analysis by flow cytometry indicated that selenium blocked cell cycle progression at multiple transition points after 24 hours and induced apoptosis after 48 hours. The Affymetrix GeneChip was used to profile the gene expression changes that might mediate these cellular events. Immediately before growth inhibition became evident in selenium-treated cells, a number of cyclins and CDKs were found to be depressed. These changes were accompanied by an increased expression of CDK inhibitors and other regulatory molecules that are known to reduce the activation of CDKs. Additionally, selenium also decreased the expression of genes involved in S phase transition, DNA synthesis and mitosis. Alterations in the transcript signal of many of these genes were confirmed at the protein level. Of particular interest is GADD153, a gene well documented to play an essential role in cell cycle control and apoptosis. The reasons for focusing on GADD153 are (a) it is one of the most highly modulated genes by selenium; (b) the induction occurs early and persists following selenium exposure; (c) as a transcription factor and a dimerization partner to other C/EBP and ATF family of proteins, it is an upstream target and is likely to modulate the transcription of many genes; and (d) the increase of GADD153 is observed in 4 different prostate cancer cell lines. The goal of this project is to investigate the role of GADD153 in contributing to the molecular effects of selenium. The research plan consists of 4 aims. Aim 1 is to determine the DNA binding activity of GADD153 in selenium-treated cells, and to identify the genes modulated directly by GADD153. Aim 2 is to characterize the dimerization partners of GADD153 following exposure to selenium. Aim 3 is to evaluate the changes in cellular responsiveness to selenium in the presence of antisense GADD153. Aim 4 is to study the transcriptional control of GADD153 by selenium. The proposed research is thus designed to examine systemically the impact of GADD153 induction as a result of selenium treatment.