Abstract
The recombinant kringle domain of urokinase (UK1) has been shown to inhibit angiogenesis and brain tumor growth in vivo. To avoid limitations in application due to mass production of recombinant protein, we attempted to develop a novel peptide inhibitor from UK1 sequence consisting of 83 amino acids that contains α-helices, loops and β-sheets. We dissected UK1 sequence to seven peptides based on structure and amino acid characteristics, and examined the anti-angiogenic activities for the constructed peptides. Among the tested peptides, UP-7 most potently inhibited the proliferation and migration of endothelial cells (ECs) in vitro, and also potently inhibited in vivo angiogenesis in the mouse matrigel plug assay. Such anti-angiogenic activities were not exerted by the scrambled peptide. At molecular level, UP-7 inhibited growth factor-induced phosphorylation of FAK and ERK1/2. It also suppressed formation of stress fibers and focal adhesions and also inhibited the attachment and spreading of ECs onto immobilized fibronectin. In a lung cancer animal model xenografted with non-UP-7-sensitive NCI-H460 cells, systemic treatment of UP-7 effectively suppressed tumor growth through inhibition of angiogenesis. Interestingly, breast cancer cells such as LM-MDA-MB-231 cells were moderately sensitive to UP-7 in proliferation differently from other cancer cells. UP-7 also inhibited migration, invasion and FAK phosphorylation of LM-MDA-MB-231 cells. Accordingly, UP-7 potently inhibited lung metastatic growth of LM-MDA-MB-231 cells in an experimental metastasis model. Taken together, these results suggest that novel peptide UP-7 can be effectively used for treatment of breast cancer metastatic growth through inhibition of angiogenesis and invasion.
Highlights
Metastasis is the main cause of mortality in most cancer patients including breast cancer patient [1]
Tumor cell migration is a key process for metastasis, and the process is regulated through cytoskeletal and cell extracellular matrix (ECM) adhesion remodeling mediated by signal [3, 4]
We found that a novel peptide UP-7 derived from extended antiparallel β-sheet structure of UK1 is the most potent anti-angiogenic fragment www.impactjournals.com/oncotarget among UK1 derived peptides
Summary
Metastasis is the main cause of mortality in most cancer patients including breast cancer patient [1]. It occurs through a multistep process including detachment of primary tumor cells, degradation of basement membranes, migration, invasion, adhesion, and proliferation at secondary site [2]. Tumor cell migration is a key process for metastasis, and the process is regulated through cytoskeletal and cell extracellular matrix (ECM) adhesion remodeling mediated by signal [3, 4]. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays an important role in integrin and growth factor mediated signaling. Fibronectin plays a role in creation of the premetastatic niche before metastasis [10]
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