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Oncotarget. 2018 Jan 10;9(11):9951-9962. doi: 10.18632/oncotarget.24131. eCollection 2018 Feb 9.

Urokinase-derived peptide UP-7 suppresses tumor angiogenesis and metastasis through inhibition of FAK activation.

Kim HK1,2,3, Naidansuren P1,2,3, Lee SW1,2,3, Kim RK4, Lee SJ4, Lee SK5, Hong YK1, Joe YA1,2,3.

Author information

1
Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, 06519, Republic of Korea.
2
Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, 06519, Republic of Korea.
3
Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, 06519, Republic of Korea.
4
Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Republic of Korea.
5
Department of Oral Pathology, College of Dentistry, Kangnung National University, Gangneung, Gangwon-do, 25457, Republic of Korea.

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.

KEYWORDS:

angiogenesis inhibitor; breast cancer; metastasis; peptide; urokinase-type plasminogen activator

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