Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78.
Kringle 5 (K5) of human plasminogen has been shown to inhibit angiogenesis by inducing the apoptosis of proliferating endothelial cells. Peptide regions around the lysine-binding pocket of K5 largely mediate these effects, particularly the peptide PRKLYDY, which we show to compete with K5 for the binding to endothelial cells. The cell surface binding site for K5 that mediates these effects has not been defined previously. Here, we report that glucose-regulated protein 78, exposed on cell surfaces of proliferating endothelial cells as well as on stressed tumor cells, plays a key role in the antiangiogenic and antitumor activity of K5. We also report that recombinant K5-induced apoptosis of stressed HT1080 fibrosarcoma cells involves enhanced activity of caspase-7, consistent with the disruption of glucose-regulated protein 78-procaspase-7 complexes. These results establish recombinant K5 as an inhibitor of a stress response pathway, which leads to both endothelial and tumor cell apoptosis.
Davidson
Don J
DJ
Department of Cancer Research, Abbott Laboratories, Abbott Park, Illinois 60064, USA. don.j.davidson@abbott.com
Haskell
Catherine
C
Majest
Sandy
S
Kherzai
Abdullah
A
Egan
David A
DA
Walter
Karl A
KA
Schneider
Andrew
A
Gubbins
Earl F
EF
Solomon
Larry
L
Chen
Zhebo
Z
Lesniewski
Rick
R
Henkin
Jack
J
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001665:Binding Sites; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010958:Plasminogen / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D011994:Recombinant Proteins; C491499:plasminogen kringle 5; D010958:Plasminogen