Signal transduction mediated by endostatin directly modulates cellular function of lung cancer cells in vitro.
Endostatin (ED) is a carboxyl-terminal fragment of collagen XVIII with strong antiangiogenic activity. ED has been considered as a highly specific inhibitor of endothelial cell proliferation and migration through interaction with its receptor on the surface of endothelial cells. Recently, direct antitumor effects of ED in colon cancer cells and head and neck squamous cell carcinoma cells has been reported. However, its effect on lung cancer cells has not been clarified. The purpose of the present study was to determine the effect of ED on in vitro lung cancer cell function and to identify its receptor on lung cancer cells. We revealed that alpha5 integrin is capable of being a functional ED receptor among several integrins that are expressed on murine lung cancer (Lewis lung cancer [LLC]) cells. We further demonstrated that the ED-integrin interaction modulates various in vitro biological functions of LLC cells as we revealed that immobilized ED helps in LLC cell adhesion and migration in an integrin-dependent manner. Furthermore, ED inhibited LLC cell proliferation and induced apoptosis. Interestingly, ED did not demonstrate any antiproliferative activity against the other murine lung cancer cell line, KLN205, that lacks alpha5 integrin but binds to immobilized ED through the beta1 integrin. In addition, the binding of ED to alpha5 integrin on LLC cells induced phosphorylation of focal adhesion kinase. Taken together, these results suggest that the interaction between ED and alpha5 integrin may play an important role in lung cancer cell function.
Cui
Ri
R
Department of Respiratory Medicine and Research Institute for Diseases of Old Age, Juntendo University, School of Medicine, Tokyo, Japan. cri@med.juntendo.ac.jp
Ohashi
Rina
R
Takahashi
Fumiyuki
F
Yoshioka
Masakata
M
Tominaga
Shigeru
S
Sasaki
Shinichi
S
Gu
Tao
T
Takagi
Yumiko
Y
Takahashi
Kazuhisa
K
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D043169:Endostatins / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D039482:Integrin alpha5 / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D039482:Integrin alpha5; D051416:Focal Adhesion Protein-Tyrosine Kinases