PSMA, Nutritional Target for Prostate Cancer Prevention

PSMA，预防前列腺癌的营养目标

• 批准号: 6617426
• 负责人: Warren D. Heston
• 金额: $ 30.79万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 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 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6617426
• 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是一种在人体内高表达的前列腺癌抗原，在大多数前列腺癌中呈高表达。我们发现PSMA是一种独特的叶酸水解酶。PSMA除了是一种对多聚谷氨酸具有高亲和力的叶酸水解酶外，还经历内化并被转运到溶酶体室，因此也可能在多聚谷氨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有关，在致癌过程中对致癌物的敏感性增加，在表达与癌症发展相关的突变基因的转基因模型中，叶酸也可以改变癌症的发展。PSMA的小鼠同源物在小鼠的前列腺中不表达。正常的小鼠前列腺癌的发病率也很低。在PSA启动子/增强子的控制下，我们培育出了在前列腺中强烈表达PSMA的小鼠。我们发现这些小鼠在大约9个月大的时候，前列腺增生和PIN的发生率很高，特别是在前列腺的腹侧和外侧。表达一种缺乏叶酸水解酶活性的PSMA的转基因动物不会表现出这些变化。我们假设PSMA作为叶酸水解酶的功能是导致前列腺异常组织结构增加的原因，我们建议进行一些研究，以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。 前列腺是一种低水平增殖的组织。叶酸的变化被认为对正在增殖的细胞有重大影响。最近对人类前列腺的研究表明，诸如前列腺上皮内萎缩(PIA)之类的疾病实际上是高度增殖的。因为还没有为小鼠前列腺建立PIA模型的方法，我们将使用具有主导作用基因的转基因动物来驱动增殖，例如大T抗原或c-Myc。这两种动物都在合理的时间框架内发生肿瘤，我们将在这些前列腺肿瘤模型中确定PSMA表达和叶酸调节对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，无论是否进行饮食叶酸操作，是否给予高度特异的高亲和力PSMA抑制剂。我们将测量血清、红细胞和组织叶酸，以及多配子凝集程度、SAM/SAH、比率以及组织对放射性标记叶酸的摄取和滞留。我们将通过阵列分析来确定组织病理学的变化，并确定PSMA在小鼠前列腺中的表达对前列腺基因表达的影响。将验证那些显示最大变化的变化，并通过原位杂交确定显示这些变化的前列腺细胞。由于PSMA可能会增加前列腺癌的易感性，这些研究可能表明，PSMA抑制剂或叶酸操作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。