PAI-1 介导 16K 泌乳素的抗血管生成和抗纤维蛋白溶解作用。
PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin.
机构信息
1] Molecular Angiogenesis Laboratory, Interdisciplinary Cluster in Applied Genoproteomics (GIGA) Research Center, University of Liège, Liège, Belgium. [2].
1] Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands. [2] Department of Radiotherapy, VU University Medical Center, Amsterdam, the Netherlands.
出版信息
Nat Med. 2014 Jul;20(7):741-7. doi: 10.1038/nm.3552. Epub 2014 Jun 15.
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.
催乳素（16K PRL）的 N 端片段通过损害血管生成来抑制肿瘤生长，但潜在机制尚不清楚。在这里，我们发现 16K PRL 结合了纤维蛋白溶解抑制剂纤溶酶原激活物抑制剂-1（PAI-1），已知 PAI-1 会促进肿瘤血管生成和生长。PAI-1 的缺失消除了 16K PRL 的抗肿瘤和抗血管生成作用。PAI-1 结合三元复合物 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 的抗纤维蛋白溶解活性，16K PRL 还可以防止小鼠发生血栓栓塞，并促进动脉血栓溶解。因此，16K PRL 通过 PAI-1-uPA-uPAR 复合物发出信号，损害肿瘤血管生成和生长，通过抑制 PAI-1 的抗纤维蛋白溶解活性，促进血栓溶解。
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