Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

被引：112

作者：

Dai, Xiaoyang ^{[1
,2
]}

Yan, Juan ^{[1
,3
]}

Fu, Xuhong ^{[1
]}

Pan, Qiuming ^{[1
]}

Sun, Danni ^{[1
]}

Xu, Yuan ^{[4
]}

Wang, Jiang ^{[5
]}

Nie, Litong ^{[6
]}

Tong, Linjiang ^{[1
]}

Shen, Aijun ^{[1
]}

Zheng, Mingyue ^{[4
]}

Huang, Min ^{[1
]}

Tan, Minjia ^{[6
]}

Liu, Hong ^{[5
]}

Huang, Xun ^{[1
]}

Ding, Jian ^{[1
]}

Geng, Meiyu ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai, Peoples R China

[2] Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou, Zhejiang, Peoples R China

[3] Univ Chinese Acad Sci, Beijing, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai, Peoples R China

[5] Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai, Peoples R China

[6] Chinese Acad Sci, Shanghai Inst Mat Med, Chem Prote Ctr, Shanghai, Peoples R China

来源：

CLINICAL CANCER RESEARCH | 2017年 / 23卷 / 20期

关键词：

NONSTEROIDAL ANTIINFLAMMATORY DRUGS; COLORECTAL-CANCER; BREAST-CANCER; COLON-CANCER; INDUCED APOPTOSIS; GROWTH-FACTOR; CELLS; RISK; SULFATE; SUPPRESSES;

D O I：

10.1158/1078-0432.CCR-17-0242

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. (C)2017 AACR.

引用

页码：6267 / 6278

页数：12

共 49 条

[21] DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo [J].