Anti-cancer Activity and Mechanism of ADAMTS-1 Fragments

ADAMTS-1片段的抗癌活性及机制

• 批准号: 7104086
• 负责人: Qin Yu
• 金额: $ 0.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2006-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7104086
• 关键词: metastasis; neoplasm /cancer; neoplastic growth

DESCRIPTION (provided by applicant): ADAMTS-1 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs-1) contains the metalloproteinase and thrombospondin type I (TSP-1) like motifs, and plays important roles in organogenesis, tissue remodeling, and tumorigenesis. However, the exact role of ADAMTS-1 and the underlying mechanism of its involvement in tumor growth and metastasis have not been established. We have shown that ADAMTS-1 undergoes auto-proteolytic cleavage and that full- length ADAMTS-1 and the ADAMTS-1 fragments that contain the TSP-1 domains display pro- and anti-tumor activity, respectively. Full-length ADAMTS-1 promotes shedding of heparin-binding EGF (HB-EGF) and amphiregulin (AR) transmembrane precursors, which in turn promote tumor cell proliferation/survival and tumor angiogenesis, suggesting that ADAMTS-1 is an attractive target for cancer therapy. On the contrary, the ADAMTS-1 fragments that contain the TSP-1 domains displayed potent anti-tumor activity and inhibit activity of soluble HB-EGF and AR. We hypothesize that (1) full-length ADAMTS-1 promotes tumor growth and metastasis by enhancing tumor cell proliferation/survival and tumor angiogenesis through shedding/activating HB-EGF and AR transmembrane precursors; (2) ADAMTS-1 binds to its substrates through the spacer domain directly or indirectly via heparin sulfate proteoglycans (HSPGs); (3) the spacer domain of ADAMTS-1 can be used as a dominant negative inhibitor of ADAMTS-1; and (4) anti-tumor activity of the ADAMTS-1 fragments resides in the TSP-1 domains which exert the anti-tumor activity by inhibiting bioactivity of several soluble heparin binding growth factors including HB- EGF and AR. To test these hypotheses, we will determine (1) the regions in the spacer domain of ADAMTS-1 that display dominant negative inhibitory effect and the exact segments in the TSP-1 domains that contain anti-tumor activity; (2) the mechanisms underlying the dominant negative inhibitory effect of the spacer domain and anti-tumor activity of the ADAMTS-1 fragments that contain the TSP-1 domains; and 3) whether the ADAMTS-1 fragments/Fc-fusion proteins/peptides derived from the spacer and the TSP-1 domains can be used as the effective anti-tumor agents. We have established the biochemical, molecular, and cell biology techniques and the in vivo tumor growth and metastasis models that are necessary to carry out the proposed experiments. The results obtained will provide the evidence to support that ADAMTS-1 is an important target for cancer therapy, and that the ADAMTS-1 fragments/peptides have potential to be used as the potent anti- cancer agents.

性状（申请人提供）：ADAMTS-1（一种具有血小板反应蛋白基序的去整合素和金属蛋白酶-1）含有金属蛋白酶和血小板反应蛋白I型（TSP-1）样基序，在器官形成、组织重塑和肿瘤发生中发挥重要作用。然而，ADAMTS-1的确切作用及其参与肿瘤生长和转移的潜在机制尚未建立。我们已经表明ADAMTS-1经历自身蛋白水解切割，并且全长ADAMTS-1和含有TSP-1结构域的ADAMTS-1片段分别显示促肿瘤活性和抗肿瘤活性。全长ADAMTS-1促进肝素结合EGF（HB-EGF）和双调蛋白（AR）跨膜前体的脱落，这反过来促进肿瘤细胞增殖/存活和肿瘤血管生成，表明ADAMTS-1是癌症治疗的有吸引力的靶标。相反，含有TSP-1结构域的ADAMTS-1片段显示出有效的抗肿瘤活性和抑制可溶性HB-EGF和AR的活性。我们推测：（1）全长ADAMTS-1通过释放/激活HB-EGF和AR跨膜前体，促进肿瘤细胞增殖/存活和肿瘤血管生成，从而促进肿瘤生长和转移;（2）ADAMTS-1通过间隔区直接或间接通过硫酸肝素蛋白聚糖（HSPGs）与其底物结合;（3）ADAMTS-1的间隔区结构域可作为ADAMTS-1的显性负性抑制剂;和（4）ADAMTS-1片段的抗肿瘤活性存在于TSP-1结构域，其发挥抗肿瘤活性。通过抑制几种可溶性肝素结合生长因子包括HB-EGF和AR的生物活性来抑制肿瘤活性。为了验证这些假设，我们将确定（1）ADAMTS-1间隔区中显示显性负抑制作用的区域和TSP-1结构域中包含抗肿瘤活性的确切片段;（2）ADAMTS-1间隔区的显性负抑制作用和包含TSP-1结构域的ADAMTS-1片段的抗肿瘤活性的潜在机制;以及3）来自间隔区和TSP-1结构域的ADAMTS-1片段/Fc融合蛋白/肽是否可以用作有效的抗肿瘤剂。我们已经建立了生物化学，分子和细胞生物学技术和体内肿瘤生长和转移模型，是必要的进行拟议的实验。本研究结果为ADAMTS-1作为肿瘤治疗的重要靶点，以及ADAMTS-1片段/肽作为潜在的抗癌药物提供了依据。