Aspirin inhibits cancer metastasis and angiogenesis via targeting heparanase

Purpose: <br />Recent epidemiological and clinical studies have suggested the benefit of aspirin for cancer patients, which inspired increasing efforts to demonstrate the anti-cancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anti-cancer 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 anti-cancer of aspirin.<br /><br />Experimental Design:<br /><span style="font-size: 11px;">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 anti-metastasis and anti-angiogenesis effects of aspirin. And these phenotypes were tested in B16F10 metastatic model, MDA-MB-231 metastatic model and MDA-MB-435 xenograft model.<br /></span><br />Results: <br />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.<br /><br />Conclusions:<br />In summary, the present 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 anti-cancer effects, and offers a direction for the development of small-molecule inhibitors of heparanase.

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