Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis.
Plasminogen activator inhibitor-1 (PAI-1) paradoxically enhances tumor progression and angiogenesis; however, the mechanism supporting this role is not known. Here we provide evidence that PAI-1 is essential to protect endothelial cells (ECs) from FasL-mediated apoptosis. In the absence of host-derived PAI-1, human neuroblastoma cells implanted in PAI-1-deficient mice form smaller and poorly vascularized tumors containing an increased number of apoptotic ECs. We observed that knockdown of PAI-1 in ECs enhances cell-associated plasmin activity and increases spontaneous apoptosis in vitro. We further demonstrate that plasmin cleaves FasL at Arg144-Lys145, releasing a soluble proapoptotic FasL fragment from the surface of ECs. The data provide a mechanism explaining the proangiogenic activity of PAI-1.
Division of Hematology-Oncology, Department of Pediatrics, University of Southern California and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA.
Khalid
K
Bajou
Hongjun
H
Peng
Walter E
WE
Laug
Catherine
C
Maillard
Agnes
A
Noel
Jean M
JM
Foidart
Joseph A
JA
Martial
Yves A
YA
DeClerck
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053222:Fas Ligand Protein / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009447:Neuroblastoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D058258:Serpin E2; D015843:Serpins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C524898:PLAUR protein, human; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; C524899:Plaur protein, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D019014:fas Receptor; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator