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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

187 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4663-4672
Number of pages10
JournalCancer Research
Volume65
Issue number11
DOIs
StatePublished - Jun 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Kringle 5 of human plasminogen induces apoptosis of endothelial and tumor cells through surface-expressed glucose-regulated protein 78'. Together they form a unique fingerprint.

Cite this