Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins
Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins
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DOI：
10.1182/blood-2008-12-197236
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发表时间：
2009-08-27
期刊：
影响因子：
20.3
通讯作者：
Javaherian, Kashi
中科院分区：
文献类型：
--
作者：
Lee, Tong-Young;Muschal, Stefan;Javaherian, Kashi
血管抑素是纤溶酶原的蛋白水解性片段，是一种有效的内源性抗血管生成药物。血管抑素抗血管生成和抗肿瘤作用的分子机制尚不清楚。在这里，我们报告了线粒体室是血管抑素的最终靶点。在血管抑素内化到细胞内后，线粒体中至少有两种蛋白质与这个分子结合：Krebs循环中的苹果酸脱氢酶和三磷酸腺苷合成酶。体外和体内研究揭示了血管抑素治疗的肿瘤和肿瘤内皮中关键的生存和血管生成相关蛋白的不同调控。Angiostatin通过下调线粒体bcl2的表达诱导细胞凋亡。血管抑素治疗导致c-Myc的下调和另一关键的抗血管生成蛋白-1的水平上升，从而加强了其抗肿瘤和抗血管生成的作用。进一步的证据表明，在血管抑素治疗的肿瘤中，骨髓来源的巨噬细胞的募集和渗透减少。观察到的血管抑素作用仅限于肿瘤部位，在小鼠的其他主要器官中没有观察到，表明独特的肿瘤特异性生物利用度。总之，我们的数据表明线粒体是抗血管生成治疗的新靶点，并为血管抑素的抗血管生成和抗肿瘤作用提供了机制上的见解。(血。2009；114：1987-1998)
Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow-derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin. (Blood. 2009; 114: 1987-1998)