Angiostatin antagonizes the action of VEGF-A in human endothelial cells via two distinct pathways

被引:52
作者
Chen, YH
Wu, HL
Chen, CK
Huang, YH
Yang, BC
Wu, LW [1 ]
机构
[1] Natl Cheng Kung Univ, Coll Med, Inst Mol Med, Tainan 70101, Taiwan
[2] Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan 70101, Taiwan
[3] Natl Cheng Kung Univ, Coll Med, Dept Biochem, Tainan 70101, Taiwan
[4] Natl Cheng Kung Univ, Coll Med, Dept Microbiol & Immunol, Tainan 70101, Taiwan
关键词
angiogenesis; endothelial cells; angiostatin; FasL; p53;
D O I
10.1016/j.bbrc.2003.09.081
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Angiostatin consisting of the first four-kringle domains of the plasminogen potently inhibits angiogenesis in vitro and in vivo. However, the molecular mechanism of action whereby angiostatin mediates its inhibitory effect on proliferating endothelial cells remains elusive. We therefore used the proliferating cultured human umbilical vein endothelial cells (HUVECs) promoted by vascular endothelial growth factor A to identify the endogenous signaling elements that mediate the antiangiogenic effect of angiostatin. Treatment of HUVEC with angiostatin at a concentration known to inhibit cell proliferation and induce apoptosis resulted in induction of p53-, Bax-, and tBid-mediated release of cytochrome c into the cytosol. In addition, angiostatin also activated the Fas-mediated apoptotic pathway in part via Up-regulation of FasL mRNA, down-regulation of c-Flip, and activation of caspase 3. These results suggest that the anti-angiogenic action of angiostatin is likely mediated by two distinct signaling pathways, one intrinsic mediated by p53 while the other extrinsic involved in FasL engagement and mitochondria dysfunction. (C) 2003 Elsevier Inc. All rights reserved.
引用
收藏
页码:804 / 810
页数:7
相关论文
共 42 条
[1]   Cell surface trafficking of Fas: A rapid mechanism of p53-mediated apoptosis [J].
Bennett, M ;
Macdonald, K ;
Chan, SW ;
Luzio, JP ;
Simari, R ;
Weissberg, P .
SCIENCE, 1998, 282 (5387) :290-293
[2]   Molecular mechanisms of blood vessel formation [J].
Bussolino, F ;
Mantovani, A ;
Persico, G .
TRENDS IN BIOCHEMICAL SCIENCES, 1997, 22 (07) :251-256
[3]   Kringle domains of human angiostatin - Characterization of the anti-proliferative activity on endothelial cells [J].
Cao, YH ;
Ji, RW ;
Davidson, D ;
Schaller, J ;
Marti, D ;
Sohndel, S ;
McCance, SG ;
OReilly, MS ;
Llinas, M ;
Folkman, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (46) :29461-29467
[4]   Expression of angiostatin cDNA in a murine fibrosarcoma suppresses primary tumor growth and produces long-term dormancy of metastases [J].
Cao, YH ;
O'Reilly, MS ;
Marshall, B ;
Flynn, E ;
Ji, RW ;
Folkman, J .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (05) :1055-1063
[5]   Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD [J].
Claesson-Welsh, L ;
Welsh, M ;
Ito, N ;
Anand-Apte, B ;
Soker, S ;
Zetter, B ;
O'Reilly, M ;
Folkman, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (10) :5579-5583
[6]  
Cooper BC, 2002, CLIN CANCER RES, V8, P3193
[7]   Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis [J].
Desagher, S ;
Osen-Sand, A ;
Nichols, A ;
Eskes, R ;
Montessuit, S ;
Lauper, S ;
Maundrell, K ;
Antonsson, B ;
Martinou, JC .
JOURNAL OF CELL BIOLOGY, 1999, 144 (05) :891-901
[8]   CONTROLLING THE VASCULATURE - ANGIOGENESIS, ANTI-ANGIOGENESIS AND VASCULAR TARGETING OF GENE-THERAPY [J].
FAN, TPD ;
JAGGAR, R ;
BICKNELL, R .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1995, 16 (02) :57-66
[9]  
Ferrara N, 2000, RECENT PROG HORM RES, V55, P15
[10]   Role of vascular endothelial growth factor in regulation of physiological angiogenesis [J].
Ferrara, N .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2001, 280 (06) :C1358-C1366