Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis

Br J Cancer. 2000 May;82(10):1702-8. doi: 10.1054/bjoc.2000.1207.

Abstract

Plasminogen activator inhibitor 1 (PAI-1) has been found to be a bad prognostic factor in a number of tumours but the reason has not been fully explained. The human prostate cancer cell line PC-3 and the human promyelocytic leukaemia cell line HL-60 were used in this study to determine the effect of PAI-1 on spontaneous and induced apoptosis in culture. Apoptosis was induced with camptothecin or etoposide. Addition of a stable variant of PAI-1 or wild-type PAI-1 to these cells resulted in a significant inhibition of apoptosis. In contrast, both the latent form of PAI-1 and the stable variant of PAI-1 inactivated by a specific neutralizing monoclonal antibody, or the stable variant of PAI-1 in a complex with recombinant urokinase did not inhibit apoptosis. This indicated that the inhibitory activity of PAI-1 was required for its anti-apoptotic effect but the urokinase-type plasminogen activator receptor was not involved. These findings provide an explanation for the bad prognostic correlation of high PAI-1 levels in tumours. The anti-apoptotic effect was also found in non-tumoural cells including human umbilical vein endothelial cells and the benign human breast epithelial cell line MCF-10A, suggesting that this is a novel physiologic function of PAI-1.

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / antagonists & inhibitors
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Camptothecin / antagonists & inhibitors
  • Camptothecin / pharmacology
  • DNA Fragmentation
  • Etoposide / antagonists & inhibitors
  • Etoposide / pharmacology
  • HL-60 Cells
  • Humans
  • Plasminogen Activator Inhibitor 1 / pharmacology*
  • Receptors, Cell Surface / metabolism
  • Receptors, Urokinase Plasminogen Activator
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • PLAUR protein, human
  • Plasminogen Activator Inhibitor 1
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Etoposide
  • Camptothecin