Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF-1 receptor
Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF-1 receptor
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DOI：
10.1002/ijc.24186
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发表时间：
2009-05-15
影响因子：
6.4
通讯作者：
Goetsch, Liliane
中科院分区：
文献类型：
--
作者：
Broussas, Matthieu;Dupont, Joelle;Goetsch, Liliane
IGF-1受体（IGF-1R）在许多肿瘤的发生发展中起着关键作用。单克隆抗体阻断IGF-1R轴是抑制肿瘤生长的一种有趣的方法。我们之前已经证明VC 10，一种人源化抗igf - 1r Mali，在体内表现出强大的抗肿瘤活性。然而，h7C10的作用机制尚不清楚。在这里，我们发现h7C10以剂量依赖的方式抑制igf -1诱导的IGF-1R磷酸化。此外，h7C10可抑制igf -1诱导的PI3K/AKT和MAPK通路的激活。h7C10可能抑制了igf -1诱导的细胞周期蛋白D1和E的表达，从而影响了细胞周期进程和集落形成。此外，我们证明h7C10诱导IGF-1R快速内化，导致积累到细胞质中，导致受体降解。使用溶酶体和蛋白酶体抑制剂，我们观察到IGF-1R α链和β链可以遵循不同的降解途径。因此，我们证明了h7C10的抗肿瘤特性是igf -1诱导的细胞信号传导抑制和IGF-1R水平下调的结果，这表明VC - 10可能是治疗应用的候选药物。(C) 2008 Wiley-Liss, Inc。
IGF-1 receptor (IGF-1R) plays a key role in the development of numerous tumors. Blockade of IGF-1R axis using monoclonal antibodies constitutes an interesting approach to inhibit tumor growth. We have previously shown that VC 10, a humanized anti-IGF-1R Mali, exhibited potent antitumor activity in vivo. However, mechanisms of action of h7C10 are still unknown. Here, we showed that h7C10 inhibited IGF-1-induced IGF-1R phosphorylation in a dose-dependent manner. Also, h7C10 abolished IGF-1-induced activation of PI3K/AKT and MAPK pathways. Cell cycle progression and colony formation were affected in the presence of h7C10 probably because of the inhibition of IGF-1-induced cyclin D1 and E expression. In addition, we demonstrated that h7C10 induced a rapid IGF-1R internalization leading to an accumulation into cytoplasm resulting in receptor degradation. Using lysosome and proteasome inhibitors, we observed that the IGF-1R alpha-and beta-chains could follow different degradation routes. Thus, we demonstrated that antitumoral properties of h7C10 are the result of IGF-1-induced cell signaling inhibition and down-regulation of IGF-1R level suggesting that VC 10 could be a candidate for therapeutic applications. (C) 2008 Wiley-Liss, Inc.