PSMA, a Nutritional Target for Prostate Cancer Preventi*

PSMA，预防前列腺癌的营养目标*

• 批准号: 6752506
• 负责人: Warren D. Heston
• 金额: $ 31.61万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752506
• 关键词: cancer prevention; carboxypeptidase; cell growth regulation; cell proliferation; dietary constituent; dietary supplements; enzyme inhibitors; folate; folate deficiency; gene expression; genetically modified animals; histology; immunocytochemistry; in situ hybridization; laboratory mouse; microarray technology; neoplasm /cancer genetics; nutrition aspect of cancer; nutrition related tag; prostate neoplasms; tumor antigens

DESCRIPTION (provided by applicant): Prostate-Specific Membrane Antigen, PSMA is a highly expressed prostate antigen in human, which is increased in expression in the majority of human prostate cancers. We discovered that PSMA is a unique folate hydrolase. In addition to being a folate hydrolase with high affinity for polygammaglutamated folates, PSMA undergoes internalization and is transported to the lysosomal compartment, and thus may play a role in the binding and transport of polygammaglutamated folates as well. Folates provide methyl groups in the synthesis of DNA and RNA. Folate deficiencies are associated with chromosomal damage and increased sensitivity to carcinogens in carcinogenesis and folate can also alter the development of cancer in transgenic models expressing mutant genes associated with the development of cancers. The mouse homolog of PSMA is not expressed in the mouse prostate. The normal mouse prostate also has a low incidence of prostate cancer. We generated mice that strongly express PSMA in their prostates under the control of the PSA promoter/enhancer. We find a high incidence of hyperplasia and PIN in the prostates of these mice at about 9 months of age, especially in the ventral prostate and lateral prostate. Transgenic animals made to express a form of PSMA that lack the folate hydrolase activity do not demonstrate these changes. We hypothesize that PSMA's function as a folate hydrolase is responsible for the increased abnormal histologic architecture in the prostate and we propose a number of studies to determine to what extent manipulation of dietary folate will accentuate or attenuate these histologic changes. The prostate is a tissue with a low level of proliferation. Changes in folate are thought to have their major impact in cells that are proliferating. Recent studies in the human prostate suggest that conditions such as prostate intraepithelial atrophy, PIA, are in fact highly proliferative. Because a way to model PIA is not established for the mouse prostate, we will use transgenic animals which have dominate acting genes which drive proliferation, such as the large T antigen, or c-Myc. Both of these animals develop tumors in a reasonable time frame and we will determine the extent PSMA expression and folate modulation impact tumor formation in these prostate tumor models. In our proposed studies we will utilize transgenic animals that express PSMA, large T antigen, or c-Myc with or without dietary folate manipulation, with or without administration of highly specific high affinity inhibitors of PSMA. We will measure serum, RBC, and tissue folates, and extent of polygammglutamation, SAM/SAH, ratios and tissue uptake and retention of radio labeled folate. We will determine the changes in tissue histopathology and determine the effect of PSMA expression in the mouse prostate on prostate gene expression by array analysis. Those changes exhibiting the greatest changes will be verified and the cells of the prostate demonstrating those changes determined by in-situ hybridization. As PSMA may be enhancing the prostates susceptibility to develop cancer, these studies may indicate whether either PSMA inhibitors or folate manipulation may provide an approach to reducing the impact of PSMA as a factor in abnormal prostate growth.

描述（由申请人提供）： 前列腺特异性膜抗原（PSMA）是一种在人类中高表达的前列腺抗原，在大多数人类前列腺癌中表达增加。我们发现 PSMA 是一种独特的叶酸水解酶。除了作为对多聚谷氨酸叶酸具有高亲和力的叶酸水解酶之外，PSMA 还经历内化并被转运至溶酶体区室，因此也可能在多聚谷氨酸叶酸的结合和转运中发挥作用。叶酸在 DNA 和 RNA 的合成中提供甲基。叶酸缺乏与染色体损伤以及致癌过程中对致癌物的敏感性增加有关，叶酸还可以在表达与癌症发展相关的突变基因的转基因模型中改变癌症的发展。 PSMA 的小鼠同源物在小鼠前列腺中不表达。正常小鼠前列腺的前列腺癌发病率也较低。我们培育出在 PSA 启动子/增强子控制下前列腺中强烈表达 PSMA 的小鼠。我们发现这些小鼠在 9 个月左右时前列腺增生和 PIN 的发生率很高，尤其是腹侧前列腺和外侧前列腺。表达缺乏叶酸水解酶活性的 PSMA 的转基因动物并未表现出这些变化。我们假设 PSMA 作为叶酸水解酶的功能导致前列腺中异常组织学结构的增加，并且我们提出了许多研究来确定饮食叶酸的操纵在多大程度上会加剧或减弱这些组织学变化。 前列腺是一种增殖水平较低的组织。叶酸的变化被认为对增殖的细胞有重大影响。最近对人类前列腺的研究表明，前列腺上皮内萎缩（PIA）等病症实际上是高度增殖的。由于尚未建立针对小鼠前列腺的 PIA 建模方法，因此我们将使用转基因动物，这些动物具有驱动增殖的主导作用基因，例如大 T 抗原或 c-Myc。这两种动物都在合理的时间范围内形成肿瘤，我们将确定 PSMA 表达和叶酸调节对这些前列腺肿瘤模型中肿瘤形成的影响程度。在我们提出的研究中，我们将利用表达 PSMA、大 T 抗原或 c-Myc 的转基因动物，有或没有饮食叶酸操作，有或没有施用高度特异性的高亲和力 PSMA 抑制剂。我们将测量血清、红细胞和组织叶酸，以及多聚谷氨酸化程度、SAM/SAH、比率以及放射性标记叶酸的组织摄取和保留。我们将确定组织病理学的变化，并通过阵列分析确定小鼠前列腺中 PSMA 表达对前列腺基因表达的影响。将验证那些表现出最大变化的变化，并通过原位杂交确定表现出这些变化的前列腺细胞。由于 PSMA 可能会增强前列腺患癌症的易感性，因此这些研究可能表明 PSMA 抑制剂或叶酸处理是否可以提供一种方法来减少 PSMA 作为前列腺异常生长因素的影响。