Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways
Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways
复制标题
DOI：
10.1182/blood-2003-05-1634
复制
发表时间：
2004-05-15
期刊：
影响因子：
20.3
通讯作者：
Dias, S
中科院分区：
文献类型：
--
作者：
Santos, SCR;Dias, S
除了在内皮细胞上表达之外，血管内皮生长因子受体（VEGF）也在白血病的亚群上起作用，导致维持白血病迁移和增殖的自分泌环。虽然最近的证据表明，VEGF支持造血干细胞的生存通过一个内部循环，自分泌刺激VEGFR-2（KDR）促进白血病生长的分子机制还没有得到很好的理解。在这里，我们表明急性髓系原发性白血病和细胞系，VEGF/KDR自分泌循环操作内部和外部。首先，我们证明了KDR是组成性磷酸化的，位于VEGF产生的白血病细胞核。用外部作用的抗VEGF抗体治疗阻断了KDR核转位并抑制了核因子K B（NF-κ B; p65和c-rel）活化。相反，KDR特异性细胞内抑制剂未能阻断KDR核转位，但抑制了丝裂原活化蛋白激酶（MAPK）/Erk和磷脂酰肌醇3-激酶/AKT通路的组成性激活。值得注意的是，单独用抗VEGF抗体治疗对细胞存活几乎没有影响，而内部抑制剂诱导白血病细胞凋亡，并且2种药物一起和与化疗一起产生协同效应，比单独使用任一种药物更大程度地降低细胞存活。我们的研究结果表明，内部和外部的VEGF/KDR自分泌环调节白血病生存通过不同的机制，并表明，阻断两者可能具有治疗潜力。(C)2004年，美国血液学会。
Besides being expressed on endothelial cells, vascular endothelial growth factor receptors (VEGFRs) are also functional on subsets of leukemias, resulting in autocrine loops that sustain leukemia migration and proliferation. While recent evidence suggests that VEGF supports hematopoietic stem cell survival via an internal loop, the molecular mechanisms whereby autocrine stimulation of VEGFR-2 (KDR) promotes leukemia growth are not well understood. Here we show on acute myeloid primary leukemias and cell lines that VEGF/KDR autocrine loops operate both internally and externally. First, we demonstrate that KDR is constitutively phosphorylated and located at the nucleus of VEGF-producing leukemias. Treatment with anti-VEGF antibody, which acts externally, blocked KDR nuclear translocation and inhibited nuclear factor K B (NF-kappaB; p65 and c-rel) activation. In contrast, a KDR-specific intracellular inhibitor failed to block KDR nuclear translocation, but inhibited the constitutive activation of mitogen activated protein kinase (MAPK)/Erk and the phosphatidylinositol 3-kinase/AKT pathways. Notably, treatment with the anti-VEGF antibody alone had little effect on cell survival, while the internal inhibitor induced leukemia apoptosis, and the 2 drugs produced synergistic effects, together and with chemotherapy, reducing cell survival to a larger extent than either agent alone. Our results demonstrate that internal and external VEGF/KDR autocrine loops regulate leukemia survival via different mechanisms, and suggest that blocking both may have therapeutic potential. (C) 2004 by The American Society of Hematology.