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

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

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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.

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.

PMID:
18835034
PMCID:
PMC2630529
DOI:
10.1016/j.ccr.2008.08.012
[Indexed for MEDLINE]
Free PMC Article

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