Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27kip1 enhancement, and disruption of binding to the extracellular matrix
Anti-CD26 monoclonal antibody-mediated G1-S arrest of human renal clear cell carcinoma Caki-2 is associated with retinoblastoma substrate dephosphorylation, cyclin-dependent kinase 2 reduction, p27kip1 enhancement, and disruption of binding to the extracellular matrix
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DOI：
10.1158/1078-0432.ccr-06-0361
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发表时间：
2006-06-01
影响因子：
11.5
通讯作者：
Morimoto, Chikao
中科院分区：
文献类型：
--
作者：
Inamoto, Teruo;Yamochi, Tadanori;Morimoto, Chikao
目的：CD 26是一种分子量为110 kDa的细胞表面糖蛋白，通过与细胞内关键蛋白的结合在肿瘤发生中发挥作用。在这份报告中，我们表明，可溶性抗CD 26单克隆抗体（mAb）的结合抑制人肾癌细胞在体外和体内experiments.Experimental设计的生长抑制抗CD 26单克隆抗体进行了评估，使用增殖试验和细胞周期分析。使用抗CD 26 mAb、化学抑制剂、显性阴性或组成型活性形式的特异性信号传导分子评价CD 26相关通路。结果：体外实验表明，抗CD 26单抗可诱导G1-S期细胞阻滞，并伴有p27（kip 1）表达增强、细胞周期蛋白依赖性激酶2表达下调和视网膜母细胞瘤底物去磷酸化。此外，我们的数据表明，增强p27（kip 1）的表达依赖于Akt活性的衰减。抗CD 26 mAb还内化细胞表面CD 26，导致与胶原蛋白和纤连蛋白的结合减少。实验表明，抗CD 26单克隆抗体治疗大大抑制肿瘤的荷瘤小鼠的肿瘤生长，从而提高survival.Conclusions：两者合计，我们的数据强烈表明，抗CD 26单克隆抗体治疗可能具有潜在的临床应用CD 26阳性肾细胞癌。
Purpose: CD26 is a 110-kDa cell surface glycoprotein with a role in tumor development through its association with key intracellular proteins. In this report, we show that binding of soluble anti-CD26 monoclonal antibody (mAb) inhibits the growth of the human renal carcinoma cells in both in vitro and in vivo experiments.Experimental Design: Growth inhibition by anti-CD26 mAb was assessed using proliferation assay and cell cycle analysis. Anti-CD26 mAb, chemical inhibitors, dominant-negative, or constitutively active forms of specific signaling molecules were used to evaluate CD26-associated pathways. The in vivo growth-inhibitory effect of anti-CD26 mAb was also assessed in a human renal carcinoma mouse xenograft model.Results: In vitro experiments show that anti-CD26 mAb induces G(1)-S cell cycle arrest associated with enhanced p27(kip1) expression, down-regulation of cyclin-dependent kinase 2, and dephosphorylation of retinoblastoma substrate. Moreover, our data show that enhanced p27(kip1) expression is dependent on the attenuation of Akt activity. Anti-CD26 mAb also internalizes cell surface CD26, leading to decreased binding to collagen and fibronectin. Experiments with a mouse xenograft model involving human renal carcinoma cells show that anti-CD26 mAb treatment drastically inhibits tumor growth in tumor-bearing mice, resulting in enhanced survival.Conclusions: Taken together, our data strongly suggest that anti-CD26 mAb treatment may have potential clinical use for CD26-positive renal cell carcinomas.