A prostate secretory protein94-derived synthetic peptide PCK3145 inhibits VEGF signalling in endothelial cells: Implication in tumor angiogenesis
A prostate secretory protein94-derived synthetic peptide PCK3145 inhibits VEGF signalling in endothelial cells: Implication in tumor angiogenesis
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DOI：
10.1002/ijc.21615
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发表时间：
2006-05-01
影响因子：
6.4
通讯作者：
Annabi, B
中科院分区：
文献类型：
--
作者：
Lamy, S;Ruiz, MT;Annabi, B
我们之前观察到PSP94的氨基酸31-45（PCK3145）对应的合成肽可以减少体内前列腺肿瘤的生长。此外，最近结束的一项针对激素难治性前列腺癌患者的 IIa 期临床试验表明，PCK3145 下调血浆基质金属蛋白酶 (MMP)-9 的水平，这是一种参与转移和肿瘤血管生成的 MMP。我们研究的目的是探讨PCK3145作用的分子机制以及该肽是否可以拮抗肿瘤新生血管形成。我们发现，在大鼠前列腺癌的同基因体内模型中，在 PCK3145 治疗的动物中，内皮细胞 (EC) 特异性 CD31（肿瘤血管密度标志物）的表达降低了 43%。在体外，PCK3145 以剂量依赖性方式特异性拮抗 VEGF 诱导的 ERK 磷酸化以及培养物 EC (HUVEC) 中 VEGFR-2 的磷酸化。这些抗 VEGF 作用可通过 PD98059 和 PTK787 等药物抑制剂部分重现，表明 PCK3145 抑制与 VEGFR-2 相关的酪氨酸激酶活性，从而阻止通过 MAPK 级联的细胞内信号传导。此外，PCK3145 还被发现可以抑制平滑肌细胞中 PDGF 诱导的 PDGFR 磷酸化。最后，PCK3145 抑制体外 EC 管生成和 VEGF 诱导的 MMP-2 分泌，表明其作为抗血管生成剂的潜在意义。我们的研究表明，PCK3145 干扰 EC 中与 VEGF 信号轴相关的酪氨酸激酶活性。这种肽的抗血管生成特性对于患有各种癌症的患者非常有益，并可用于新型抗血管生成疗法。 (c) 2005 年 Wiley-Liss, Inc.
We have previously observed that the synthetic peptide corresponding to amino acids 31-45 (PCK3145) of PSP94 can reduce prostate tumor growth in vivo. Moreover, a recently concluded phase IIa clinical trial with patients with hormone refractory prostate cancer indicated that PCK3145 down-regulates the levels of plasma matrix metalloproteinase (MMP)-9, a MMP involved in metastasis and tumor angiogenesis. The purpose of our study was to investigate the molecular mechanisms of action of PCK3145 and whether this peptide could antagonize tumor neovascularization. We show that, in a syngeneic in vivo model of rat prostate cancer, the expression of endothelial cell (EC) specific CD31, a marker of tumor vessel density, was decreased by 43% in PCK3145-treated animals. In vitro, PCK3145 specifically antagonized in a dose-dependent manner the VEGF-induced ERK phosphorylation as well as the phosphorylation of the VEGFR-2 in culturea EC (HUVEC). These anti-VEGF effects were partly reproduced by pharmacological inhibitors such as PD98059 and PTK787, suggesting that PCK3145 inhibits the tyrosine kinase activity associated to VEGFR-2, which in turn prevents intracellular signalling through the MAPK cascade. Moreover, PCK3145 was also found to inhibit the PDGF-induced phosphorylation of PDGFR in smooth muscle cells. Finally, PCK3145 inhibited in vitro EC tubulogenesis and VEGF-induced MMP-2 secretion suggesting its potential implication as an antiangiogenic agent. Our study demonstrates that PCK3145 interferes with the tyrosine kinase activity associated with VEGF signalling axis in EC. The antiangiogenic properties of this peptide could be highly beneficial and exploited in novel antiangiogenic therapies, for patients with various cancers. (c) 2005 Wiley-Liss, Inc.