This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The most critical aspect of prostate cancer is the progression to advanced disease, which is coincident with the conversion from an androgen-dependent to an androgen-independent state. We have recently demonstrated that the levels of the cell-surface insulin-like growth factor-I (IGF-I) receptor (IGF-IR) are reduced in metastatic vs. non-metastatic tumor samples and prostate cancer cell lines. Importantly, restoration of IGF-IR levels in the metastatic prostate cancer cell lines attenuates tumorigenecity and metastatic potential in nude mouse xenografts. These studies suggest that the decrease in IGF-IR expression is a critical aspect of disease progression. We have now found that introduction of a wild-type androgen receptor (AR) into the M12 metastatic prostate cancer cell line results in concomitant reduced tumorigenecity and up-regulation of IGF-IR expression. We hypothesize that the upregulation of IGF-IR expression represents an entirely novel, nongenomic, ligand-independent action of the AR, and one that may be relevant to the loss of androgen responsiveness in the progression to advanced disease.
Specific Aims : (1) Assess the effect of the AR on polysomal loading of IGF-IR mRNA and the expression of heterologous IGF-IR 5'-UTR/luciferase fusion constructs, (2) define the structural components of the IGF-IR 5'-UTR sequence that are necessary for AR-mediated translational control, (3) define the domains of the AR that are involved in translational regulation, and (4) identify additional translational targets of the AR using microarray analysis.
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