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

Abstract

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.

• Authors: Jai-Hyun Kim, Dong Soon Choi, Ok-Hee Lee, Seung-Hyun Oh, Scott M Lippman, Ho-Young Lee
• Journal: Blood (Blood) Vol. 118 Issue 9 Pg. 2622-31 (Sep 01 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21551235 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inhibitors
• EGR1 protein, human
• ELK1 protein, human
• Early Growth Response Protein 1
• IGFBP3 protein, human
• Insulin-Like Growth Factor Binding Protein 3
• Neoplasm Proteins
• Recombinant Fusion Proteins
• ets-Domain Protein Elk-1
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Angiogenesis Inhibitors (metabolism, pharmacology, therapeutic use)
• Animals
• Carcinoma (blood supply, drug therapy, pathology)
• Carcinoma, Non-Small-Cell Lung (blood supply, drug therapy, pathology)
• Cell Line, Tumor
• Cells, Cultured (cytology, drug effects)
• Chick Embryo
• Early Growth Response Protein 1 (genetics, metabolism)
• Endothelial Cells (cytology, drug effects)
• Enzyme Activation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Head and Neck Neoplasms (blood supply, drug therapy, pathology)
• Humans
• Insulin-Like Growth Factor Binding Protein 3 (metabolism, pharmacology, therapeutic use)
• Lung Neoplasms (blood supply, drug therapy, pathology)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Neovascularization, Pathologic (drug therapy)
• Promoter Regions, Genetic (drug effects)
• Recombinant Fusion Proteins (pharmacology, therapeutic use)
• Specific Pathogen-Free Organisms
• Transcription, Genetic (drug effects)
• Xenograft Model Antitumor Assays
• ets-Domain Protein Elk-1 (metabolism)