Neutral Endopeptidase inactivation in advanced prostate

晚期前列腺中的中性肽链内切酶失活

• 批准号: 6894775
• 负责人: David M. Nanus
• 金额: $ 31.87万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894775
• 关键词: androgens; bombesin like peptide; carcinogenesis; cell growth regulation; cell migration; cell proliferation; chimeric proteins; clinical research; endothelin; focal adhesion kinase; gene expression; genetic transcription; human subject; immunoprecipitation; laboratory mouse; male; monoclonal antibody; neoplasm /cancer genetics; neoplastic process; neprilysin; neurotensin; prostate neoplasms; prostate specific antigen; recombinant proteins; tissue /cell culture; tumor suppressor genes; tumor suppressor proteins

DESCRIPTION (provided by applicant): Numerous studies indicate that neuropeptide growth factors contribute to the development and progression of prostate cancer. Neutral endopeptidase 24.11 (NEP, CALLA, CD10) is a cell-surface peptidase that inactivates a variety of neuropeptides implicated in prostate cancer, including bombesin, endothelin-1 (ET-1) and neurotensin. We first reported that NEP expression is decreased in a subset of primary and metastatic prostate cancers, and that NEP expression is in part regulated by androgen and decreases with androgen-withdrawal. In our research over this past grant period, we have characterized the androgen regulation of the NEP gene, demonstrated that replacement of NEP using either exogenous recombinant NEP or overexpression of cell-surface NEP inhibits prostate cancer cell growth, cell migration and tumorigenicity, and have identified at least three distinct mechanisms by which NEP exerts a tumor suppressive effect, including 1) catalytic inactivation of NEP's neuropeptide substrates, 2) indirectly associating with phosphatidylinositol 3-kinase (P13-K) protein and inhibiting the interaction of P13-K with focal adhesion kinase (FAK), and 3) directly associating with and stabilizing the PTEN tumor suppressor gene protein. These data suggest that the NEP protein normally functions to regulate prostate epithelial cell growth, and that loss of NEP expression may contribute to prostate cancer growth and progression. In this renewal application, we propose to continue to define the mechanisms of NEP anti-tumor effects in prostate cancer cells, to more thoroughly decipher the regulation of NEP expression, and to study the potential of NEP as therapy using a novel fusion protein in which NEP is linked to a monoclonal antibody which specifically targets prostate cancer cells. These proposed studies should provide significant new knowledge on the multiple functions of cell-surface peptidases with NEP as a prototype, and more clearly define the involvement of NEP in the development and progression of prostate cancer.

描述（申请人提供）：大量研究表明神经肽生长因子参与前列腺癌的发生和进展。中性内肽酶24.11 （NEP， CALLA, CD10）是一种细胞表面肽酶，可使多种与前列腺癌相关的神经肽失活，包括bombesin，内皮素-1 （ET-1）和神经紧张素。我们首先报道了NEP表达在原发性和转移性前列腺癌的一个亚群中降低，NEP表达部分受雄激素调节，并随着雄激素的减少而降低。在过去的研究中，我们描述了NEP基因的雄激素调控，证明使用外源性重组NEP或细胞表面过表达NEP替代NEP可抑制前列腺癌细胞生长、细胞迁移和致瘤性，并确定了NEP发挥肿瘤抑制作用的至少三种不同机制，包括1)NEP神经肽底物的催化失活；2)间接与磷脂酰肌醇3-激酶（P13-K）蛋白相关并抑制P13-K与focal adhesion kinase （FAK）的相互作用；3)直接与PTEN肿瘤抑制基因蛋白相关并稳定PTEN。这些数据表明，NEP蛋白在正常情况下调节前列腺上皮细胞的生长，NEP表达的缺失可能导致前列腺癌的生长和进展。在这项更新申请中，我们建议继续确定NEP在前列腺癌细胞中的抗肿瘤作用机制，更彻底地破译NEP的表达调控，并使用NEP与特异性靶向前列腺癌细胞的单克隆抗体相结合的新型融合蛋白来研究NEP作为治疗方法的潜力。这些拟开展的研究将为以NEP为原型的细胞表面肽酶的多种功能提供重要的新认识，并更清晰地界定NEP在前列腺癌发生发展中的作用。

项目成果

Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase

• DOI: 10.1038/sj.onc.1209586
• 发表时间: 2006-09
• 期刊: Oncogene
• 影响因子: 8
• 作者: Rong Zheng;A. Iwase;R. Shen;O. Goodman;N. Sugimoto;Y. Takuwa;Daniel Lerner;D. Nanus

Synergistic activation of the androgen receptor by bombesin and low-dose androgen.

铃蟾肽和低剂量雄激素协同激活雄激素受体。

• 发表时间: 2002
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research.
• 作者: Dai,Jie;Shen,Ruoqian;Sumitomo,Makoto;Stahl,Rosalyn;Navarro,Daniel;Gershengorn,MarvinC;Nanus,DavidM
• 通讯作者: Nanus,DavidM

Tumor-suppressive effects of neutral endopeptidase in androgen-independent prostate cancer cells.

• 发表时间: 2001-05
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Jie Dai;R. Shen;Makoto Sumitomo;Jonathan S. Goldberg;Yiping Geng;Daniel Navarro;Su Xu;J. Koutcher;Mark Garzotto;C. T. Powell;D. Nanus

Methylation of the neutral endopeptidase gene promoter in human prostate cancers.

人类前列腺癌中中性肽链内切酶基因启动子的甲基化。

• 发表时间: 2000
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research.
• 作者: Usmani,BA;Shen,R;Janeczko,M;Papandreou,CN;Lee,WH;Nelson,WG;Nelson,JB;Nanus,DM
• 通讯作者: Nanus,DM

Multiple androgen response elements cooperate in androgen regulated activity of the type 1 neutral endopeptidase promoter.

多个雄激素反应元件在 1 型中性内肽酶启动子的雄激素调节活性中协同作用。

• DOI: 10.1016/j.mce.2006.07.004
• 发表时间: 2006
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Zheng,Rong;Shen,Ruoqian;GoodmanJr,OscarB;Nanus,DavidM
• 通讯作者: Nanus,DavidM