Molecular mechanisms involved in activity of h7C10, a humanized monoclonal antibody, to IGF-1 receptor.

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 h7C10, a humanized anti-IGF-1R Mab, 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 h7C10 could be a candidate for therapeutic applications.
Mesh Terms:
Animals, Antibodies, Monoclonal, Base Sequence, Cyclins, Female, Flow Cytometry, Humans, Immunoprecipitation, Lysosomes, MAP Kinase Signaling System, Mice, Microscopy, Fluorescence, Phosphorylation, RNA, Small Interfering, Receptor, IGF Type 1, Retinoblastoma Protein, Transplantation, Heterologous, Ubiquitination
Int. J. Cancer
Date: May. 15, 2009
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