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.
Publication types
- Research Support, N.I.H., Extramural
MeSH terms
- 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*
Substances
- 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