Up-Regulation of Connective Tissue Growth Factor in Endothelial Cells by the Microtubule-Destabilizing Agent Combretastatin A-4
Up-Regulation of Connective Tissue Growth Factor in Endothelial Cells by the Microtubule-Destabilizing Agent Combretastatin A-4
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DOI：
10.1158/1541-7786.mcr-08-0292
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发表时间：
2009-02-01
影响因子：
5.2
通讯作者：
Goppelt-Struebe, Margarete
中科院分区：
文献类型：
--
作者：
Samarin, Jana;Rehm, Margot;Goppelt-Struebe, Margarete
用combretastatin a -4 phosphate (CA-4P)（一种优先靶向肿瘤血管的微管不稳定化合物）培养微血管内皮细胞，改变细胞形态并诱导高尔基堆积散射。同时，CA-4P上调结缔组织生长因子（CTGF/CCN2），这是一种具有抗血管生成特性的多效因子。与秋水仙碱或诺可达唑等其他微管靶向药物的作用相反，CTGF的上调仅在稀疏细胞中检测到，这些细胞没有嵌入细胞单层。此外，CA-4P诱导内皮细胞中CTGF的表达，在基底膜凝胶上形成管状结构。CA-4P上调CTGF依赖于Rho激酶信号，当p42/44丝裂原活化蛋白激酶被抑制时，CTGF上调。此外，FoxO转录因子被鉴定为内皮细胞中CTGF表达的有效调节因子。通过抑制磷脂酰肌醇3-激酶/AKT信号通路激活FoxO转录因子，导致ca - 4p介导的CTGF诱导协同增加。因此，ca - 4p介导的CTGF表达通过抑制激酶途径而增强，激酶途径是新型抗肿瘤药物的靶点。因此，低浓度CA-4P对CTGF的上调可能发生在新形成的肿瘤血管中，并有助于体内观察到CA-4P的微血管不稳定和抗血管生成作用。[j] .癌症杂志，2009;7(2):180-8。
Incubation of microvascular endothelial cells with combretastatin A-4 phosphate (CA-4P), a microtubule-destabilizing compound that preferentially targets tumor vessels, altered cell morphology and induced scattering of Golgi stacks. Concomitantly, CA-4P up-regulated connective tissue growth factor (CTGF/CCN2), a pleiotropic factor with antiangiogenic properties. In contrast to the effects of other microtubule-targeting agents such as colchicine or nocodazole, up-regulation of CTGF was only detectable in sparse cells, which were not embedded in a cell monolayer. Furthermore, CA-4P induced CTGF expression in endothelial cells, forming tube-like structures on basement membrane gels. Up-regulation of CTGF by CA-4P was dependent on Rho kinase signaling and was increased when p42/44 mitogen-activated protein kinase was inhibited. Additionally, FoxO transcription factors were identified as potent regulators of CTGF expression in endothelial cells. Activation of FoxO transcription factors by inhibition of phosphatidylinositol 3-kinase/AKT signaling resulted in a synergistic increase in CA-4P-mediated CTGF induction. CA-4P-mediated expression of CTGF was thus potentiated by the inhibition of kinase pathways, which are targets of novel antineoplastic drugs. Up-regulation of CTGF by low concentrations of CA-4P may thus occur in newly formed tumor vessels and contribute to the microvessel destabilization and antiangiogenic effects of CA-4P observed in vivo. (Mol Cancer Res 2009;7(2):180-8)