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Antiangiogenic antitumor activities of IGFBP-3 are mediated by IGF-independent suppression of Erk1/2 activation and Egr-1-mediated transcriptional events

 Jai-Hyun Kim  ;  Dong Soon Choi  ;  Ok-Hee Lee  ;  Seung-Hyun Oh  ;  Scott M. Lippman  ;  Ho-Young Lee 
 BLOOD, Vol.118(9) : 2622-2631, 2011 
Journal Title
Issue Date
Angiogenesis Inhibitors/metabolism ; Angiogenesis Inhibitors/pharmacology* ; Angiogenesis Inhibitors/therapeutic use ; Animals ; Carcinoma/blood supply ; Carcinoma/drug therapy* ; Carcinoma/pathology ; Carcinoma, Non-Small-Cell Lung/blood supply ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cells, Cultured/cytology ; Cells, Cultured/drug effects ; Chick Embryo ; Early Growth Response Protein 1/genetics* ; Early Growth Response Protein 1/metabolism ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Enzyme Activation/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects* ; Head and Neck Neoplasms/blood supply ; Head and Neck Neoplasms/drug therapy* ; Head and Neck Neoplasms/pathology ; Humans ; Insulin-Like Growth Factor Binding Protein 3/metabolism ; Insulin-Like Growth Factor Binding Protein 3/pharmacology* ; Insulin-Like Growth Factor Binding Protein 3/therapeutic use ; Lung Neoplasms/blood supply ; Lung Neoplasms/drug therapy* ; Lung Neoplasms/pathology ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors* ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists & inhibitors* ; Mitogen-Activated Protein Kinase 3/metabolism ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neovascularization, Pathologic/drug therapy* ; Promoter Regions, Genetic/drug effects* ; Recombinant Fusion Proteins/pharmacology ; Recombinant Fusion Proteins/therapeutic use ; Specific Pathogen-Free Organisms ; Transcription, Genetic/drug effects* ; Xenograft Model Antitumor Assays ; ets-Domain Protein Elk-1/metabolism*
Most antiangiogenic therapies currently being evaluated in clinical trials target the vascular endothelial growth factor pathway; however, the tumor vasculature can acquire resistance to vascular endothelial growth factor-targeted therapy by shifting to other angiogenesis mechanisms. Insulin-like growth factor binding protein-3 (IGFBP-3) has been reported to suppress tumor growth and angiogenesis by both IGF-dependent and IGF-independent mechanisms; however, understanding of its IGF-independent mechanisms is limited. We observed that IGFBP-3 blocked tumor angiogenesis and growth in non-small cell lung cancer and head and neck squamous cell carcinoma. Conditioned media from an IGFBP-3-treated non-small cell lung cancer cell line displayed a significantly decreased capacity to induce HUVEC proliferation and aortic sprouting. In cancer cells, IGFBP-3 directly interacted with Erk1/2, leading to inactivation of Erk1/2 and Elk-1, and suppressed transcription of early growth response protein 1 and its target genes, basic fibroblast growth factor and platelet-derived growth factor. These data suggest that IGF-independent Erk1/2 inactivation and decreased IGFBP-3-induced Egr-1 expression block the autocrine and paracrine loops of angiogenic factors in vascular endothelial and cancer cells. Together, these findings provide a molecular framework of IGFBP-3's IGF-independent antiangiogenic antitumor activities. Future studies are needed for development of IGFBP-3 as a new line of antiangiogengic cancer drug.
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Yonsei Authors
Lee, Ok Hee(이옥희)
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