Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China.
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China.
Clin Cancer Res. 2017 Oct 15;23(20):6267-6278. doi: 10.1158/1078-0432.CCR-17-0242. Epub 2017 Jul 14.
Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin. A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model. This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner. In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase. .
最近的流行病学和临床研究表明，阿司匹林对癌症患者有益，这激发了人们越来越多的努力来证明阿司匹林的抗癌能力，并揭示其背后的分子机制。然而，阿司匹林的抗癌活性和相关机制在很大程度上仍然未知。本研究旨在证实这一观察结果，更重要的是，研究潜在的阿司匹林抗癌作用的靶标。本研究使用均相时间分辨荧光（HTRF）测定法来检测阿司匹林对乙酰肝素酶的影响。通过链霉亲和素下拉、表面等离子体共振（SPR）测定法和分子对接来鉴定乙酰肝素酶为阿司匹林结合蛋白。通过 Transwell、大鼠主动脉环和鸡胚绒毛尿囊膜模型来评估阿司匹林的抗转移和抗血管生成作用，并在 B16F10 转移模型、MDA-MB-231 转移模型和 MDA-MB-435 异种移植模型中测试这些表型。本研究确定了乙酰肝素酶，一种参与癌症转移和血管生成的致癌细胞外基质酶，是阿司匹林的潜在靶标。我们发现阿司匹林直接结合到乙酰肝素酶的 Glu225 区域并抑制其酶活性。阿司匹林以依赖于乙酰肝素酶的方式阻碍肿瘤转移、血管生成和生长。总之，本研究首次阐明了乙酰肝素酶是阿司匹林的靶标。它为更好地理解阿司匹林在抗癌作用中的机制提供了思路，并为开发乙酰肝素酶小分子抑制剂提供了方向。
