PAT-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin
PAT-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin
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DOI：
10.1038/nm.3552
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发表时间：
2014-07-01
期刊：
影响因子：
82.9
通讯作者：
Struman, Ingrid
中科院分区：
文献类型：
--
作者：
Bajou, Khalid;Herkenne, Stephanie;Struman, Ingrid
催乳素n端片段（16K PRL）通过损害血管生成来抑制肿瘤生长，但其潜在机制尚不清楚。在这里，我们发现16K PRL结合纤维蛋白溶解抑制剂纤溶酶原激活物抑制剂-1 (PAI-1)，已知其在背景下促进肿瘤血管生成和生长。PAI-1的缺失使16K PRL的抗肿瘤和抗血管生成作用失效。PAI-1结合三元络合物PAI-1-尿激酶型纤溶酶原激活物(uPA)-uPA受体（uPAR），从而发挥抗血管生成作用。通过抑制PAI-1的抗纤溶活性，16K PRL还能保护小鼠抗血栓栓塞，促进动脉血栓溶解。因此，通过PAI-1- upa - upar复合物的信号传导，16K PRL损害肿瘤血管化和生长，并通过抑制PAI-1的抗纤溶活性，促进溶栓。
The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.