We have identified a 44-kDa protein (p44) that interacts with the androgen receptor (AR) and regulates androgen-driven gene expression in the prostate gland. P44 in the nucleus functions as a transcriptional cofactor to inhibit cell growth via G1/G0 cell cycle arrest and to be required for differentiation of epithelial cells. Therefore, loss of the p44 gene leads to retarded differentiation and hyper proliferation of epithelial cells in mouse prostate. The p44-mediated growth arrest is relieved when the p44 protein is transported from the nucleus to the cytoplasm, which occurs in prostatic intraepithelial neoplasia (PIN) and in prostate cancer. Consistently with these observations, we found that the p44 protein localizes in the cytoplasm of prostate epithelial cells during early stage of the prostate development, when epithelial cells are rapidly proliferating. In contrast, p44 localizes in the nucleus in the adult prostate, when epithelial cells are fully differentiated and not dividing. Thus, the p44 cytoplasm translocation is the first essential step that leads to proliferation of prostate epithelial cells in the aging prostate and therefore, provides a novel target site for prostate cancer prevention. By screening a small chemical compound library, we have identified 6 novel compounds that inhibited p44 cytoplasm translocation. The proposed research will study the dose response and specificity for identified compounds and evaluate these compounds in inhibition of p44 cytoplasm translocation in two cell culture systems. The cytotoxicity of the identified compounds will also be investigated. In addition, we will test whether inhibition of the p44 cytoplasm localization by identified compounds suppresses growth of prostate epithelial and prostate cancer cells. We will also determine whether this inhibitory effect by identified compounds on cell proliferation is through regulation of p44 subcellular translocation. By using the tissue-specific p44 gene knockout mouse, tissue-specific transgenic mouse, mouse primary epithelial cells, and prostate cancer cell lines, roles of identified compounds in the control of p44 subcellular transportation and of cell proliferation and differentiation will be studied. These analyses will provide a basis for developing novel agents for chemoprevention of prostate cancer.
Our studies reveal that the p44 subcellular localization determines proliferation or differentiation of prostate epithelial cells and contributes to the aging-related prostate tumorigenesis. The proposed research will test whether small chemical compounds that inhibit p44 cytoplasm translocation suppress proliferation and enhance differentiation of prostate epithelial cells. The proposed research will open the door for future work on the chemoprevention of prostate cancer.
