Chemoprevention is an attractive approach to prostate cancer control. Several agents have been identified to be effective in reducing risk;among these are finasteride and selenium. In two independent phase III studies, treatment with finasteride or selenium decreased prostate cancer by 25% or 50%, respectively, although in the selenium trial, prostate cancer was not the primary endpoint. Finasteride is a competitive inhibitor of 5a-reductase, an enzyme responsible for the irreversible conversion of testosterone to dihydrotestosterone (DHT). Preliminary results from our laboratory showed that selenium depresses androgen receptor (AR)abundance, AR trans-activating activity and the expression of AR-regulated genes. Based on the above information, we propose to test the following hypotheses. Hypothesis #1: Since finasteride and selenium target different steps along the androgen signaling pathway, combining these two agents is likely to produce a cooperative or synergistic effect in prostate cancer prevention. Hypothesis #2: Disrupting the interaction between the DHT-AR complex with FOXO1A is critical for the anticancer effect of finasteride/selenium. FOXO1A is physically bound to and negatively regulated by DHT-AR. Through the mechanism of decreasing DHT by finasteride and AR availability by selenium, FOXO1A is expected to be liberated. As a transcription factor, FOXO1A induces the expression of a number of pro-apoptotic genes. The research plan consists of four specific aims.
Aim 1 : To determine (a) whether the combination of finasteride/selenium results in a further suppression of androgen signaling when compared to the single agent, and (b) whether finasteride has other effects on AR signaling beyond its known function of blocking 5a-reductase.
Aim 2 : To investigate the role of FOXO1A, a transcription factor negatively regulated by AR, in mediating the anticancer effect of finasteride and selenium.
Aim 3 : To study (a) the activation of initiator caspases and executioner caspases by finasteride or selenium, or both;and (b) whether restoration of AR signaling reverses the effect of each agent on caspase activation and caspase-mediated apoptosis.
Aim 4 : To validate the anticancer efficacy of finasteride/selenium and the accompanying molecular changes (information obtained from Aims 1to 3) in human prostate cancer xenograft models.
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