Kringle 5 of Human Plasminogen Induces Apoptosis of Endothelial and Tumor Cells through Surface-Expressed Glucose-Regulated Protein 78

Don J. Davidson, Catherine Haskell, Sandy Majest, Abdullah Kherzai, David A. Egan, Karl A. Walter, Andrew Schneider, Earl F. Gubbins, Larry Solomon, Zhebo Chen, Rick Lesniewski, Jack Henkin
2005 Cancer Research  
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
more » ... s 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. (Cancer Res 2005; 65(11): 4663-72) Requests for reprints: Don Davidson,
doi:10.1158/0008-5472.can-04-3426 pmid:15930284 fatcat:srkpjqqzlnhytij446vhlk4zhu