Brain-derived neurotrophic factor induces proliferation, migration, and VEGF secretion in human multiple myeloma cells via activation of MEK-ERK and PI3K/AKT signaling
Brain-derived neurotrophic factor induces proliferation, migration, and VEGF secretion in human multiple myeloma cells via activation of MEK-ERK and PI3K/AKT signaling
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DOI：
10.1007/s13277-010-0016-x
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发表时间：
2010-04-01
期刊：
影响因子：
--
通讯作者：
Chen, Lei
中科院分区：
文献类型：
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作者：
Sun, Chun-yan;Hu, Yu;Chen, Lei
本研究探讨了脑源性神经营养因子（BDNF）在多发性骨髓瘤（MM）中不同生物学效应的信号通路。[H-3]胸腺嘧啶核苷掺入法检测BDNF对MM细胞系和原代骨髓瘤细胞增殖的影响。采用transwell迁移实验观察BDNF对MM细胞迁移的影响。通过逆转录-聚合酶链反应和酶联免疫吸附试验分析BDNF刺激血管内皮生长因子（VEGF）的产生。通过蛋白质印迹法确定响应于BDNF而激活的信号转导通路。在MM细胞中，BDNF以剂量依赖性方式诱导VEGF。用BDNF刺激MM细胞导致磷脂酰肌醇3-激酶（PI 3 K）/Akt和MEK-细胞外信号调节蛋白激酶途径的激活。使用特定的信号转导抑制剂，我们证明，MEK是必需的BDNF诱导的增殖，而激活PI 3 K是必需的BDNF刺激的迁移和VEGF的生产。BDNF影响MM细胞中介导生长、迁移和VEGF分泌的不同细胞信号传导途径。我们的观察提供了新的治疗策略的框架，在MM中靶向BDNF信号级联。
This study investigated the signaling pathways involved in the different biological effects of brain-derived neurotrophic factor (BDNF) in multiple myeloma (MM). The effects of BDNF on proliferation of MM cell lines and primary myeloma cells were examined by [H-3] thymidine incorporation assay. The effects of BDNF on MM cells migration were studied by transwell migration assay. Stimulation by BDNF of vascular endothelial growth factor (VEGF) production was analyzed by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. The signal-transduction pathways that are activated in response to BDNF were determined by Western blots. VEGF is induced by BDNF in a dose-dependent manner in MM cells. Stimulation of MM cells with BDNF led to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the MEK-extracellular signal-regulated protein kinase pathways. Using specific signal-transduction inhibitors, we demonstrated that MEK is required for BDNF-induced proliferation, whereas activation of PI3K is required for BDNF-stimulated migration and VEGF production. BDNF affects different cell signaling pathways mediating growth, migration, and VEGF secretion in MM cells. Our observations provided the framework for novel therapeutic strategies targeting BDNF signaling cascades in MM.