Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis

Cancer Cell. 2008 Oct 7;14(4):324-34. doi: 10.1016/j.ccr.2008.08.012.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Fas Ligand Protein / metabolism*
  • Fibrinolysin / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic / metabolism
  • Neuroblastoma / blood supply
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Peptide Fragments / metabolism
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Cell Surface / metabolism
  • Receptors, Urokinase Plasminogen Activator
  • Serpin E2
  • Serpins / deficiency
  • Serpins / genetics
  • Serpins / metabolism*
  • Time Factors
  • Urokinase-Type Plasminogen Activator / metabolism
  • fas Receptor / metabolism

Substances

  • FAS protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • PLAUR protein, human
  • Peptide Fragments
  • Plasminogen Activator Inhibitor 1
  • Plaur protein, mouse
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • SERPINE1 protein, human
  • Serpin E2
  • Serpine2 protein, mouse
  • Serpins
  • fas Receptor
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator