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.
Broussas
Matthieu
M
Centre d'Immunologie Pierre Fabre, 5 Avenue Napoléon III, BP 60497, Saint-Julien-en-Genevois, France. matthieu.broussas@pierre-fabre.com
Dupont
Joëlle
J
Gonzalez
Alexandra
A
Blaecke
Aline
A
Fournier
Mathilde
M
Corvaïa
Nathalie
N
Goetsch
Liliane
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001483:Base Sequence; D016213:Cyclins / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D008247:Lysosomes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1 / Q000276:immunology* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D014183:Transplantation, Heterologous; D054875:Ubiquitination
D000911:Antibodies, Monoclonal; D016213:Cyclins; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D017526:Receptor, IGF Type 1