Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways
Zoledronate inhibits endothelial cell adhesion, migration and survival through the suppression of multiple, prenylation-dependent signaling pathways
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DOI：
10.1111/j.1538-7836.2006.02259.x
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发表时间：
2007-01-01
影响因子：
10.4
通讯作者：
Rueegg, C.
中科院分区：
文献类型：
--
作者：
Hasmim, M.;Bieler, G.;Rueegg, C.
背景资料：最近的证据表明，唑来膦酸盐，一种用于治疗骨吸收增加的含氮双膦酸盐，可能具有抗血管生成活性。由唑来膦酸调节的内皮细胞信号传导事件在很大程度上仍然难以捉摸。目的：这项工作的目的是确定由唑来膦酸盐抑制内皮细胞的信号转导事件，并负责其生物学效应。研究方法：将人脐静脉内皮细胞（HUVEC）暴露于唑来膦酸盐、类异戊二烯类似物（即法尼醇和香叶基香叶醇）和各种信号传导抑制剂，并表征其对粘附、存活、迁移、肌动蛋白细胞骨架和信号传导事件的影响。结果如下：唑来膦酸盐减少Ras异戊烯化，Ras和RhoA转运到膜，并持续ERK 1/2磷酸化和肿瘤坏死因子（TNF）诱导的JNK磷酸化。类异戊二烯类似物减弱唑来膦酸对HUVEC粘附、肌动蛋白应力纤维和粘着斑、迁移和存活的影响。在唑来膦酸存在下，类异戊二烯类似物还恢复了暴露于TNF的HUVEC中的Ras异戊二烯化、RhoA向膜的移位、维持FAK和ERK 1/2磷酸化并防止蛋白激酶B（PK B）和JNK磷酸化的抑制。Rock（一种RhoA靶点，介导肌动蛋白纤维形成）、磷脂酰肌醇3-激酶（一种PKB激活剂）、MEK 1/2（一种ERK 1/2激活剂）和JNK的药理学抑制作用概括了唑来膦酸盐的个体效应，与这些分子和途径的参与及其在唑来膦酸盐效应中的抑制作用一致。结论：这项工作表明，唑来膦酸盐抑制HUVEC粘附，存活，迁移和肌动蛋白应力纤维的形成，通过干扰蛋白质异戊二烯化，并确定ERK 1/2，JNK，岩石，FAK和PKB的激酶受唑来膦酸盐的异戊二烯化依赖性的方式。
Background: Recent evidence indicates that zoledronate, a nitrogen-containing bisphosphonate used to treat conditions of increased bone resorption, may have anti-angiogenic activity. The endothelial cells signaling events modulated by zoledronate remain largely elusive. Objectives: The aim of this work was to identify signaling events suppressed by zoledronate in endothelial cells and responsible for some of its biological effects. Methods: Human umbilical vein endothelial cells (HUVEC) were exposed to zoledronate, isoprenoid analogs (i.e. farnesol and geranylgeraniol) and various inhibitors of signaling, and the effect on adhesion, survival, migration, actin cytoskeleton and signaling events characterized. Results: Zoledronate reduced Ras prenylation, Ras and RhoA translocation to the membrane, and sustained ERK1/2 phosphorylation and tumor necrosis factor (TNF) induced JNK phosphorylation. Isoprenoid analogs attenuated zoledronate effects on HUVEC adhesion, actin stress fibers and focal adhesions, migration and survival. Isoprenoid analogs also restored Ras prenylation, RhoA translocation to the membrane, sustained FAK and ERK1/2 phosphorylation and prevented suppression of protein kinase B (PKB) and JNK phosphorylation in HUVEC exposed to TNF in the presence of zoledronate. Pharmacological inhibition of Rock, a RhoA target mediating actin fiber formation, phosphatidylinositol 3-kinase, an activator of PKB, MEK1/2, an activator of ERK1/2, and JNK, recapitulated individual zoledronate effects, consistent with the involvement of these molecules and pathways and their inhibition in the zoledronate effects. Conclusions: This work has demonstrated that zoledronate inhibits HUVEC adhesion, survival, migration and actin stress fiber formation by interfering with protein prenylation and has identified ERK1/2, JNK, Rock, FAK and PKB as kinases affected by zoledronate in a prenylation-dependent manner.