The first but not the second thrombospondin type 1 repeat of ADAMTS5 functions as an angiogenesis inhibitor.
Angiogenesis is critical for tumour growth and metastasis where factors that regulate this process are potential targets for development of anti-cancer drugs. In this study, we show that the first TSR domain of the extracellular matrix protease ADAMTS5, unlike the second TSR, has anti-angiogenic activities where it inhibits endothelial cell tube formation on Matrigel, reduces cell proliferation and attachment, while promoting cell apoptosis and migration, all in a dose-dependent manner. Furthermore, it influences the architecture of endothelial cells by disrupting actin stress fibres and reducing focal adhesions, likely via suppressing RhoA activation. TSR1 of ADAMTS5 is therefore a novel anti-angiogenic peptide and could serve as a prototype for future development into anti-cancer drugs.
Sharghi-Namini
Soheila
S
Department of Biological Sciences, Faculty of Science, National University of Singapore, Block S2, Science Drive 4, Singapore 117543, Singapore.
Fan
Huapeng
H
Sulochana
K N
KN
Potturi
Padma
P
Xiang
Wei
W
Chong
Yap-Seng
YS
Wang
Zhengyuan
Z
Yang
He
H
Ge
Ruowen
R
D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D000071116:ADAMTS5 Protein; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007797:Laminin / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects; D019700:Thrombospondin 1 / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D010455:Peptides; D011509:Proteoglycans; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human