Evaluation of chemical compounds for the potential to prevent prostate cancer

评估化合物预防前列腺癌的潜力

基本信息

批准号：
8007540
负责人：
ZHENGXIN WANG
金额：
$ 7.9万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8007540
关键词：
Adult Aging Androgen Receptor Androgens Area Cell Culture System Cell Cycle Arrest Cell Nucleus Cell Proliferation Cells Chemicals Chemoprevention Cytoplasm Development Dose Epithelial Epithelial Cell Proliferation Epithelial Cells Evaluation Event Future Gene Expression Genes Growth Knockout Mice LNCaP Large T Antigen Libraries Malignant neoplasm of prostate Mediating Mus PC3 cell line Process Proliferating Prostate Prostatic Intraepithelial Neoplasias Proteins Regulation Research Research Design Role Screening procedure Site Specificity Staging Temperature Testing Tissues Toxic effect Transgenic Mice Transportation Work age related aged base cancer cell cancer chemoprevention cancer initiation cell growth cofactor cytotoxicity innovation men novel prevent prostate cancer prevention research study response therapeutic target tissue culture tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：我们已经确定了与雄激素受体（AR）相互作用并调节前列腺中雄激素驱动的基因表达的44 kDa蛋白（p44）。细胞核中的p44充当转录辅因子，可通过G1/G0细胞周期停滞抑制细胞生长，并且是分化上皮细胞所必需的。因此，p44基因的丧失导致小鼠前列腺中上皮细胞的分化和超增殖。当p44蛋白从核从核转运到细胞质时，p44介导的生长停滞将缓解，该细胞质发生在前列腺上皮内肿瘤（PIN）和前列腺癌中。与这些观察结果一致，我们发现p44蛋白在前列腺发育的早期阶段（当上皮细胞迅速增殖时）将p44蛋白定位在前列腺上皮细胞的细胞质中。相比之下，当上皮细胞完全分化且不分裂时，p44定位于成年前列腺的核中。因此，p44细胞质易位是导致衰老前列腺中前列腺上皮细胞增殖的第一步，因此为预防前列腺癌提供了新的目标部位。通过筛选一个小型化合物库，我们发现了6种抑制P44细胞质易位的新型化合物。拟议的研究将研究已鉴定化合物的剂量反应和特异性，并评估这些化合物在两个细胞培养系统中抑制p44细胞质易位时的这些化合物。还将研究确定化合物的细胞毒性。此外，我们将测试通过鉴定出的化合物抑制p44细胞质定位是否抑制前列腺上皮和前列腺癌细胞的生长。我们还将确定通过鉴定化合物对细胞增殖的这种抑制作用是否通过调节p44亚细胞易位。通过使用组织特异性的p44基因基因敲除小鼠，组织特异性的转基因小鼠，小鼠原代上皮细胞和前列腺癌细胞系，将研究鉴定化合物在控制p44亚细胞运输以及细胞增殖和分化中的作用。这些分析将为开发新型药物的化学预防化学预防癌的基础。