Inamoto Teruo, Yamochi Tadanori, Ohnuma Kei, Iwata Satoshi, Kina Shinichiro, Inamoto Sakiko, Tachibana Masaaki, Katsuoka Yoji, Dang Nam H, Morimoto Chikao
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Japan.
Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3470-7. doi: 10.1158/1078-0432.CCR-06-0361.
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.
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.
In vitro experiments show that anti-CD26 mAb induces G1-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.
Taken together, our data strongly suggest that anti-CD26 mAb treatment may have potential clinical use for CD26-positive renal cell carcinomas.
CD26是一种110 kDa的细胞表面糖蛋白，通过与关键细胞内蛋白结合在肿瘤发展中发挥作用。在本报告中，我们表明可溶性抗CD26单克隆抗体（mAb）的结合在体外和体内实验中均抑制人肾癌细胞的生长。
使用增殖测定和细胞周期分析评估抗CD26 mAb的生长抑制作用。使用抗CD26 mAb、化学抑制剂、特定信号分子的显性负性或组成型活性形式来评估与CD26相关的途径。还在人肾癌小鼠异种移植模型中评估了抗CD26 mAb的体内生长抑制作用。
体外实验表明，抗CD26 mAb诱导G1-S细胞周期停滞，与p27（kip1）表达增强、细胞周期蛋白依赖性激酶2下调以及视网膜母细胞瘤底物去磷酸化有关。此外，我们的数据表明p27（kip1）表达增强依赖于Akt活性的减弱。抗CD26 mAb还使细胞表面CD26内化，导致与胶原蛋白和纤连蛋白的结合减少。用人肾癌细胞进行的小鼠异种移植模型实验表明，抗CD26 mAb治疗可显著抑制荷瘤小鼠的肿瘤生长，从而提高生存率。
综上所述，我们的数据强烈表明抗CD26 mAb治疗可能对CD26阳性肾细胞癌具有潜在的临床应用价值。
