Integrin alpha(v)beta(3)-mediated activation of apoptosis.
The alpha(v)beta(3) integrin mediates endothelial cell binding to the extracellular matrix and transduces an intracellular signal promoting survival of endothelial cells and various tumor cells. While the alpha(v)beta(3) integrin-mediated survival signal has been shown to be adhesion dependent, a thorough analysis has not been performed comparing the biochemical effects of antagonist binding to alpha(v)beta(3) integrin with the effects induced by the growth of cells in suspension. In this study we demonstrate that expression of alpha(v)beta(3) integrin in human embryonic kidney 293 cells transfers the alpha(v)beta(3) integrin survival pathway to an epithelial cell line. Furthermore, we show that alpha(v)beta(3) integrin-expressing cells respond differently to alpha(v)beta(3) integrin-specific antagonist treatment and growth in suspension conditions. Treatment with the alpha(v)beta(3) antagonist echistatin resulted in an apoptotic response occurring prior to cell detachment and was not observed in either suspended cells or antagonist-treated suspended cells. These data suggest that the death induced by antagonist binding to alpha(v)beta(3) integrin results in an apoptotic signal with different kinetics than the apoptotic signal induced by matrix detachment (anoikis). Since aberrant alpha(v)beta(3) integrin expression in tumor models is thought to play a role in tumor cell survival, these data have implications for the use of alpha(v)beta(3) antagonists as anti-tumor agents.
Brassard
D L
DL
Department of Tumor Biology, Schering-Plough Research Institute, K-15-4-4600, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
Maxwell
E
E
Malkowski
M
M
Nagabhushan
T L
TL
Kumar
C C
CC
Armstrong
L
L
D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000378:metabolism; D016895:Culture Media, Serum-Free; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008970:Molecular Weight; D009842:Oligopeptides / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection
D017304:Annexin A5; D003374:Coumarins; D016895:Culture Media, Serum-Free; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D010455:Peptides; D019030:Receptors, Vitronectin; C115495:aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; C057986:echistatin; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases