Journal
CANCER CELL
Volume 14, Issue 4, Pages 324-334Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2008.08.012
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Funding
- NIH [CA81403, CA129377]
- The Saban Research Institute of Childrens Hospital Los Angeles
- Postdoctoral Travel Fellowship Award from the Rose and Jean Hoguet Foundation
- Fondation Cancerologique Saint Michel
- Fondation Braconier-Lamarche
- Centre Anticancereux of Liege
- Federal Office for Scientific Research (Belgium)
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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.
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