Bradykinin-Induced Cell Migration and COX-2 Production Mediated by the Bradykinin B1 Receptor in Glioma Cells
Bradykinin-Induced Cell Migration and COX-2 Production Mediated by the Bradykinin B1 Receptor in Glioma Cells
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DOI：
10.1002/jcb.22520
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发表时间：
2010-05-01
影响因子：
4
通讯作者：
Wong, Kar-Lok
中科院分区：
文献类型：
--
作者：
Lu, Dah-Yuu;Leung, Yuk-Man;Wong, Kar-Lok
缓激肽产生并作用于损伤和炎症部位。最近的报道还表明，缓激肽选择性地调节血液肿瘤屏障的通透性。然而，缓激肽诱导胶质瘤迁移的分子机制和病理作用尚不清楚。神经胶质瘤是最常见的原发性成人脑肿瘤，由于肿瘤细胞容易扩散到大脑的其他区域，因此预后不良。在本研究中，我们发现缓激肽增加胶质瘤细胞的迁移和环氧化酶-2（考克斯-2）的表达。选择性考克斯-2抑制剂NS-398可减弱缓激肽介导的迁移。此外，缓激肽B1受体（B1 R）激动剂可模拟胶质瘤细胞运动性和考克斯-2表达的增加，而B1 R拮抗剂可显著抑制这种增加。缓激肽介导的迁移减弱磷酸肌醇3-激酶（PI-3激酶）/AKT抑制剂LY 294002和渥曼青霉素。缓激肽刺激还增加PI-3激酶的p85亚基和AKT的丝氨酸473的磷酸化。缓激肽与AP-1抑制剂丹参酮HA和姜黄素的治疗也减少了考克斯-2的表达和胶质瘤细胞的迁移。此外，缓激肽的治疗也诱导神经胶质瘤细胞中c-Jun的磷酸化。荧光素酶报告基因构建体中的AP-1启动子分析表明，缓激肽增加AP-1转录活性，并被LY 294002和渥曼青霉素抑制。缓激肽介导的迁移的一个潜在机制是考克斯-2的转录上调和B1 R受体、PI-3激酶、AKT、c-Jun和AP-1途径的激活。J.细胞。110：141-150，2010. (C)2010 Wiley-Liss，Inc.
Bradykinin is produced and acts at the site of injury and inflammation. Recent reports have also shown that bradykinin selectively modulates blood-tumor barrier permeability. However, the molecular mechanisms and pathologic roles underlying bradykinin-induced glioma migration remain unclear. Glioma is the most common primary adult brain tumor, with a poor prognosis because of the ease with which tumor cells spread to other regions of the brain. In this study, we found that bradykinin increases the cell migration and expression of cyclo-oxygenase-2 (COX-2) in glioma cells. Bradykinin-mediated migration was attenuated by the selective COX-2 inhibitor NS-398. Moreover, increased motility of glioma cells and expression of COX-2 were mimicked by a bradykinin B1 receptor (B1R) agonist and markedly inhibited by a B1R antagonist. Bradykinin-mediated migration was attenuated by phosphoinositide 3-kinase (PI-3 kinase)/AKT inhibitors LY 294002 and wortmannin. Bradykinin stimulation also increased the phosphorylation of the p85 subunit of PI-3 kinase and serine 473 of AKT. Treatment of bradykinin with AP-1 inhibitors Tanshinone HA and curcumin also reduced COX-2 expression and glioma cell migration. Moreover, treatment of bradykinin also induced phosphorylation of c-Jun in glioma cells. AP-1 promoter analysis in the luciferase reporter construct showed that bradykinin increased AP-1 transcription activity and was inhibited by LY 294002 and wortmannin. One mechanism underlying bradykinin-directed migration is transcriptional up-regulation of COX-2 and activation of the B1R receptor, PI-3 kinase, AKT, c-Jun, and AP-1 pathways. J. Cell. Biochem. 110: 141-150, 2010. (C) 2010 Wiley-Liss, Inc.