NEUTRAL ENDOPEPTIDASE INACTIVATION IN ADVANCED PROSTATE

晚期前列腺中的中性内肽酶失活

• 批准号: 2896750
• 负责人: David M. Nanus
• 金额: $ 29.79万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896750
• 关键词: Mus musculus; androgens; carcinogenesis; cell growth regulation; cell line; cell proliferation; gene expression; genetic transcription; laboratory mouse; neoplastic process; neprilysin; prostate neoplasms; recombinant proteins; tissue /cell culture; transcription factor

Neutral endopeptidase 24.11 (NEP) is a cell-surface peptidase expressed by prostatic epithelial cells which cleaves and inactivates neuropeptides implicated in the growth of androgen-independent prostate cancer (PC). We show that NEP expression and catalytic activity are lost in vitro in androgen-independent but not androgen-dependent PC cell lines. In vivo, NEP protein expression is commonly decreased in cancer cells of metastatic PC specimens from patients with androgen-independent but not androgen-dependent PC. Overexpression of NEP in androgen- independent PC cells or incubation with recombinant NEP inhibits PC cell growth. Furthermore, in androgen-dependent PC cells, expression of NEP is transcriptionally regulated by androgen and decreases with androgen- withdrawal. Consequently, PC cells which survive androgen-withdrawal can emerge with reduced NEP. These data suggest that decreased NEP expression, common in androgen-independent PCS, is facilitated by the elimination of androgens, and that NEP loss plays an important role in the development of androgen-independent PC by allowing PC cells to use mitogenic neuropeptides as an alternate source to androgen to stimulate cell proliferation. To thoroughly define the involvement of NEP on androgen-independent PC cells, our specific aims are (1) to explore the mechanism by which NEP inhibits cell growth; (2) to establish that the androgen response element (ARE) in the 3' end of the NEP gene is a functional ARE which enhances transcription of the NEP gene; and (3) to assess the antitumor effects of NEP in an animal model of prostate cancer by establishing that recombinant NEP can inhibit the tumorigenicity of androgen-independent PC cells in an orthotopic model of PC, and to establish that overexpression of NEP in androgen- independent PC cells inhibits the tumorigenicity of androgen-independent PC cells. These studies leading to a better understanding of the involvement of NEP in the development and progression of androgen- independent PC may ultimately provide support for novel approaches for the treatment of advanced PC.

中性内肽酶24.11（NEP）是一种细胞表面肽酶， 前列腺上皮细胞分裂并灭活 与雄激素非依赖性前列腺生长有关的神经肽 癌症（PC）。 我们发现，NEP的表达和催化活性， 在雄激素非依赖性PC细胞而非雄激素依赖性PC细胞中的体外丢失 线 在体内，NEP蛋白表达通常在癌症中降低， 来自雄激素非依赖性前列腺癌患者的转移性PC标本的细胞 而不是雄激素依赖性PC。 NEP在雄激素中的过度表达- 独立的PC细胞或与重组NEP孵育抑制PC细胞 增长 此外，在雄激素依赖性PC细胞中，NEP的表达 在转录上受雄激素调节，并随雄激素减少- 戒断 因此，雄激素戒断后存活的PC细胞 可以减少NEP。 这些数据表明， 在雄激素非依赖性PCS中常见的表达， 雄激素的消除，NEP的损失在 雄激素非依赖性PC的发展，允许PC细胞使用 促有丝分裂神经肽作为雄激素的替代来源， 细胞增殖 为了彻底界定NEP的参与， 雄激素非依赖性PC细胞，我们的具体目标是（1）探索 NEP抑制细胞生长的机制;（2）建立NEP抑制细胞生长的机制。 NEP基因3'端的雄激素反应元件（ARE）是一个雄激素受体， 增强NEP基因转录的功能性ARE;和（3） 评估NEP在前列腺动物模型中的抗肿瘤作用 通过建立重组NEP可以抑制 雄激素非依赖性PC细胞原位模型的致瘤性 的PC，并建立NEP在雄激素- 非雄激素依赖性PC细胞的致瘤性 PC细胞。 这些研究有助于更好地了解 NEP参与雄激素的发展和进展- 独立PC最终可能为新方法提供支持， 晚期PC的治疗