Over the last decade, we and others have shown that several components of the IGF axis in general, and IGFBP-3 in particular, are important determinants of prostate cancer (CaP) cell growth and death, and represent epidemiological risk factors for this disease. Much of our work has focused on the IGF-independent actions of IGFBP-3 on CaP. Concurrently, a critical role has emerged for retinoid-related receptors in cell function including neoplasia development. These two areas of research converged last year when we discovered that RXR serves as a nuclear receptor for IGFBP-3 and that ligands for RXR co-operate with IGFBP-3 in inducing CaP cell death in vitro. We have shown that IGFBP-3 modulates certain nuclear signaling pathways through its ability to bind RXR. We have also characterized an additional, rapid, effect of IGFBP-3 on apoptosis, and demonstrated it to be non-transcriptional in nature. Preliminary data suggests that IGFBP-3 displaces the orphan receptor TR3 (Nur77/NGFI-B) from RXR and leads to specific translocation of TR3 out of the nucleus. The mitochondrial translocation of TR3 is directly related to its ability to mediate cell death. We propose to investigate the roles of IGFBP-3 in modulating transcriptional and non-transcriptional signaling of RXR and RXR partners, particularly TR3, in prostate cancer models. Thus, we will test the following hypotheses: 1) IGFBP-3, TR3, and RXR control critical and synergistic growth inhibitory pathways in CaP; and RXR ligands amplify IGFBP-3-mediated growth suppression and apoptosis of CaP in vitro and in vivo. 2) Some of the effects of IGFBP-3 are mediated through an IGF-independent mechanism involving synergistic modulation of gene transcription in concert with RXR or through antagonism of signaling of RXR partners. 3) By binding RXR, IGFBP-3 modulates and participates in gene transcription events acting as a regulator of nuclear receptor function potentially affecting recruitment of members of the co-activator complex. 4) Through its ability to preferentially bind RXR, IGFBP-3 directly displaces TR3 from its co-partner resulting in mitochondrial targeting and activation of cytochrome c to effect apoptosis. Therefore, our objectives for this project are to understand the molecular basis of the interaction between the RXR, TR3, and IGFBP-3 genomic and non-genomic signaling pathways. Our approach will involve: Q Treatment of androgen-dependent and-independent CaP tissue culture models and CaP tumor xenografts-bearing SCID mice with combinations of RXR ligands and IGFBP-3 and analysis of the biological response and gene expression profiles involved in the response to these agents. II) Investigation of the effects of IGFBP-3 on the interaction between RXR and its co-activators and co-repressors. III) Analysis of the effects of IGFBP-3 on the sub-cellular localization of TR3, biological activity of TR3, and signaling via various TR3 and RXR-related response elements; and assessment of the loss of TR3 in vivo, in knockout mice, on the normal prostatic development and androgen depravation-induced apoptosis and on the progression of prostate cancer in the TRAMP mouse model of CaP. If successful our findings may validate novel targets for clinical therapy development for use in men with CaP.
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