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NEUTRAL ENDOPEPTIDASE INACTIVATION IN ADVANCED PROSTATE

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
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-06-01 至 2002-05-31

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中文摘要
翻译
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参与雄激素的发育和进展- 独立PC最终可能为新方法提供支持, 晚期PC的治疗
英文摘要
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.
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