Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase.

Abstract

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. Clin Cancer Res; 23(20); 6267-78. ©2017 AACR.

• Authors: Xiaoyang Dai, Juan Yan, Xuhong Fu, Qiuming Pan, Danni Sun, Yuan Xu, Jiang Wang, Litong Nie, Linjiang Tong, Aijun Shen, Mingyue Zheng, Min Huang, Minjia Tan, Hong Liu, Xun Huang, Jian Ding, Meiyu Geng
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 20 Pg. 6267-6278 (Oct 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28710312 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• heparanase
• Glucuronidase
• Aspirin

Topics

• Angiogenesis Inhibitors (chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Aspirin (chemistry, pharmacology)
• Cell Line, Tumor
• Chick Embryo
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Glucuronidase (antagonists & inhibitors, chemistry, metabolism)
• Humans
• Mice
• Models, Molecular
• Molecular Conformation
• Neoplasms (drug therapy, metabolism, pathology)
• Neovascularization, Pathologic (drug therapy, enzymology)
• Protein Binding
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays