NEUTRAL ENDOPEPTIDASE INACTIVATION IN ADVANCED PROSTATE

中性内肽酶24.11(NEP)是一种细胞表面表达的多肽酶 由前列腺上皮细胞裂解并失活 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的表达和催化活性是 雄激素非依赖性但非雄激素依赖性PC细胞的体外丢失 台词。在体内，NEP蛋白在癌症中的表达通常降低 雄激素非依赖型PC转移性标本中的细胞 但不是雄激素依赖型PC。NEP在雄激素中的过表达 独立PC细胞或与重组NEP孵育对PC细胞的抑制作用 成长。此外，在雄激素依赖的PC细胞中，NEP的表达 受雄激素的转录调节，并随雄激素的减少而减少- 戒烟。因此，在雄激素停用后存活的PC细胞 可以出现NEP降低的情况。这些数据表明，NEP下降 在雄激素非依赖性PCS中常见的表达是由 雄激素的消除，NEP的丢失在 允许PC细胞使用雄激素非依赖性PC的发展 促有丝分裂神经肽作为雄激素刺激的替代来源 细胞增殖。要彻底界定非执行董事在 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基因3‘端的雄激素反应元件(ARE)是一种 增强NEP基因转录的功能ARE；和(3) 在前列腺动物模型上评价NEP的抗肿瘤作用 通过建立重组NEP可以抑制癌症 雄激素非依赖性PC细胞在原位模型中的致瘤性 并建立NEP在雄激素中的过表达- 独立的PC细胞抑制雄激素非依赖性的致瘤性 PC细胞。这些研究有助于更好地理解 NEP参与雄激素的发生发展 独立PC最终可能为以下方面的新方法提供支持 晚期PC的治疗。

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.